EP1590322A1 - Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof - Google Patents

Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof

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Publication number
EP1590322A1
EP1590322A1 EP04700448A EP04700448A EP1590322A1 EP 1590322 A1 EP1590322 A1 EP 1590322A1 EP 04700448 A EP04700448 A EP 04700448A EP 04700448 A EP04700448 A EP 04700448A EP 1590322 A1 EP1590322 A1 EP 1590322A1
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Prior art keywords
alkyl
substituted
alkenyl
alkynyl
alkylene
Prior art date
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EP04700448A
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German (de)
French (fr)
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EP1590322B1 (en
Inventor
Elisabeth Defossa
Dieter Kadereit
Thomas Klabunde
Hans-Joerg Burger
Andreas Herling
Karl-Ulrich Wendt
Erich Von Roedern
Karl Schoenafinger
Alfons Enhsen
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/48—Y being a hydrogen or a carbon atom
    • C07C275/54—Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention relates to carbonylamino-substituted acyl-phenyl-urea derivatives and their physiologically tolerable salts and physiologically functional derivatives.
  • WO 9946236 (Novo Nordisk) describes carbonylamino-substituted acylphenylurea derivatives (example 1) with action in type 2 diabetes.
  • WO 00/07991 (PCT / GB99 / 02489 Astra Zeneca) describes amide derivatives as inhibitors of the formation of cytokines.
  • the invention had for its object to provide compounds with which prevention and treatment of type II diabetes is possible.
  • the compounds should in particular have a therapeutically utilizable blood sugar-lowering effect.
  • the invention therefore relates to compounds of the formula I
  • R9, R10, R11 independently of one another H, F, Cl, Br, OH, N0 2 , CN, 0- (C
  • R1, R2 independently of one another are H, (-CC 6 ) -alkyl, alkyl having OH, 0- (dC 4 ) -
  • Alkyl, NH 2) NH (-CC 4 ) -alkyl, N [(CC 6 ) -alkyl] 2 can be substituted, O- (dC 6 ) -alkyl, CO- (CrC 6 ) -alkyl, COO- ( -CC 6 ) alkyl, (dC 6 ) -A! Kylene-COOH or (dC 6 ) -alkylene-COO- (dC 6 ) -alkyl;
  • R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, O-
  • R7 H (dC 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (-C-C 4 ) -alkylene,
  • heteroaryl- (dC) -alkylene or heteroarylcarbonyl alkyl, cycloalkyl, alkylene, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OR12, COOR12, CONH 2 , CONH (C 1 -C 6 ) -alkyl, CON [ (dC 6 ) -alkyl] 2 or N (R13) (R14) can be substituted and where aryl and heteroaryl are used several times with F, Cl, Br, NO 2 , CN, 0-R12, S-R12, COOR12, N (R13 ) (R14), or (CrC 6 ) alkyl may be substituted;
  • R13, R14 independently of one another are H, (dC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) -Cycioalkyl, (C 3 -C 7 ) -Cyc.oa.kyKCrC 4 ) alkylene, COO- (CrC 4 ) alkyl, COO - ⁇ - C - ⁇ - alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (dC 6 ) alkyl, O-td-CeJ-alkyl, CF 3 , OCF 3 , COOH, COO (dC 6 ) alkyl or CONH 2 can be substituted; where R13 and R14 together with the nitrogen atom to which they are attached can form a 3-7 membered, saturated
  • R21, R22 independently of one another H, (-CC 8 ) alkyl, (C -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (CC 4 ) -alkylene, COO- (dC 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, pheny!
  • phenyl ring being up to twice with F, Cl, CN, OH, (CC 6 ) -alkyl, 0- (C 1 -C 6 ) -alkyl, CF 3 , OCF 3> COOH, COO ( dC 6 ) alkyl or CONH 2 may be substituted;
  • R5 is halogen or unsubstituted (dC 6 ) alkyl, R7 is heterocyclic radical or heteroaryl;
  • R8, R9, R10, R11 independently of one another H, F, Cl, Br, OH, NO 2 , CN, 0- (CC 6 ) -alkyl, where alkyl can be substituted several times by F, Cl or Br;
  • R, R2 H; R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, O-
  • R7 H (CC 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) aikenyl, (C 2 -C 6 ) alkynyl !, (d- C 6 ) alkylcarboxy- (CrC 6 ) alkylene, COOR12, (C 6 -C 10 ) aryl, (C 6 -C 10 ) aryl
  • Heteroarylcarbonyl wherein .
  • Alkyl, cycloalkyl, alkylene, alkenyl and alkynyl several times with F, Cl, Br, OR12, COOR12, CONH 2 , CONH (dC 6 ) -alkyl, CON [(CrC 6 ) -alkyl] 2 or N (R13) (R14) may be substituted and wherein aryl and heteroaryl are repeatedly substituted with F, Cl, Br, N0 2 , CN, 0-R12, S-R12,
  • R12 H, (-C-C ⁇ ) alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 ) alkynyl, alkyl, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OH or 0- ( dC 4 ) -alkyl may be substituted,
  • R13, R14 independently of one another H, (-CC 8 ) -alkyl, (C 2 -C 8 ) -alkenyl, (C 2 -C 8 ) -alkynyl, (C 3 -C 7 ) -cycloalkyl, (C 3 - C 7 ) -cycloalkyl- (CC 4 ) -alkylene, COO- (dC 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (dC 6 ) alkyl, 0- (CC 6 ) alkyl, CF 3 , OCF 3 ,
  • COOH, COO (CC 6 ) alkyl or CONH 2 may be substituted; where R13 and R14 together with the nitrogen atom to which they are attached can form a 3-7 membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, the heterocyclic ring having up to three times with F, Cl, Br, OH,
  • Oxo, N (R21) (R22) or (CC 4 ) alkyl may be substituted; R21, R22 independently of one another are H, (dC 8 ) -alkyl;
  • R5 is halogen or unsubstituted (dC 6 ) alkyl
  • R7 is heterocyclic radical or heteroaryl
  • R8, R9, R10, R11 independently of one another H, F or Cl;
  • R3, R5 independently of one another H, Cl, OR12, COOR12, N (R13) (R14) or (d-
  • R7 (dC 6 ) -alkyl where alkyl is repeated with F, OR12, COOR12 or
  • N (R13) (R14) may be substituted, (C 3 -C 6 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 5 ) alkylcarboxy - (C 1 -C 6 ) -alkylene, COOR12, phenyl, where phenyl can be substituted several times with F, OMe or OCF 3 , benzyl, where the phenyl ring can be substituted with OMe, pyridyl,
  • R12 is H or (d-Cs) -alkyl, where alkyl can be substituted several times by F;
  • R13, R14 independently of one another are H or (C-rC 8 ) -alkyl; and where R13 and R14 together with the nitrogen atom to which they are attached can form a 5-membered, saturated heterocyclic ring;
  • R5 is halogen or unsubstituted (dC 6 ) alkyl
  • R7 is heterocyclic radical or heteroaryl
  • the invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
  • alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 R12, R13, R14, R21 and R22 can be either straight-chain or branched.
  • radicals or substituents can occur more than once in the compounds of the formula I, for example 0-R12, they can all independently of one another have the meanings given and be the same or different.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethione, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.
  • inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid
  • organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethione, lactic, lactobionic,
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, Al- potassium metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine, or ethylenediamine.
  • Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in vitro, applications.
  • physiologically functional derivative denotes any physiologically compatible derivative of a compound of formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able (directly or indirectly) to form a compound of formula I or an active metabolite thereof.
  • the physiologically functional derivatives also include prodrugs of the compounds according to the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may or may not work themselves.
  • the compounds of the invention can also exist in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong to the scope of the invention and are a further aspect of the invention.
  • aryl radical is understood to mean a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralone, indanyl or indan-1-one-yl radical.
  • heterocyclic ring and “heterocyclic radical” used here refer to heteroaryl radicals and heterocycloalkyl radicals which are derived from 3 to 10-membered carbon rings in which one or more carbon atoms are selected from the group oxygen, sulfur and one or more atoms and nitrogen.
  • Suitable “heterocyclic rings” or “heterocyclic radicals” are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazidazolinyl, carbazidazolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5,2-dithiazinyl, dihydrofuro [2,3-b] -tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, lmid H-l
  • Pyridyl represents both 2-, 3- and 4-pyridyl.
  • Thienyl represents both 2- and 3- thienyl.
  • Furyl stands for both 2- and 3-furyl.
  • One or more benzo-fused derivatives of these heterocycles are also included.
  • the compound (s) of the formula (I) can also be administered in combination with other active ingredients.
  • the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day per kilogram of body weight, for example 3-10 mg / kg / day.
  • An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg / kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes can contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.
  • Single doses can contain, for example, from 1 mg to 10 g of the active ingredient.
  • ampoules for injections can contain, for example, from 1 mg to 100 mg
  • orally administrable single-dose formulations such as tablets or capsules, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the compounds of the formula I themselves can be used as a compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier.
  • the carrier must of course be compatible, in the sense that it is compatible with the other components of the composition and is not harmful to the health of the patient.
  • the carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active ingredient.
  • Further pharmaceutically active substances can also be present, including further compounds according to formula I.
  • Pharmaceutical compositions can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the components with pharmacologically acceptable carriers and / or auxiliaries.
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case depends on the type and severity of the to be treated State and on the type of compound used according to formula I is dependent.
  • Coated formulations and coated slow-release formulations also fall within the scope of the invention.
  • Formulations which are resistant to acid and gastric juice are preferred.
  • Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration can be present in separate units, such as capsules, capsules, lozenges or tablets, each containing a certain amount of the compound • according to formula I; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions can be prepared by any suitable pharmaceutical method comprising a step in which the active ingredient and the carrier (which can consist of one or more additional ingredients) are brought into contact.
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary.
  • a tablet can be produced by compressing or molding a powder or granulate of the compound, optionally with one or more additional components.
  • Pressed tablets can be compressed into tablets Compound in free flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (more) surface-active / dispersing agent in a suitable machine.
  • Molded tablets can be made by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for oral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they can also be administered subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be prepared by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
  • Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be prepared by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols and combinations can be used as carriers can be used by two or more of these substances.
  • the active substance. is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.
  • Suitable pharmaceutical compositions for transdermal applications can be presented as individual patches which are suitable for long-term close contact with the patient's epidermis.
  • Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is approximately 1% to 35%, preferably approximately 3% to 15%.
  • the active ingredient can be released by electrotransport or iontophoresis, as described for example in Pharmaceutical Research, 2 (6): 318 (1986).
  • the active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
  • Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221, 633), GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk A / S have been disclosed, as well as orally active hypoglycemic agents.
  • the orally active hypoglycemic active ingredients preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists,
  • Potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes, which are involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, compounds which alter the lipid metabolism such as antihyperlipidemic active substances and antilipidemic active substances, compounds which reduce food intake, PPAR and PXR agonists and active substances which are dependent on the ATP Potassium channel, the beta cells act.
  • the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
  • the compounds of the formula I are used in combination with a cholesterol absorption inhibitor, such as e.g. Ezetimibe, Tiqueside, Pamaqueside.
  • a cholesterol absorption inhibitor such as e.g. Ezetimibe, Tiqueside, Pamaqueside.
  • the compounds of the formula I are used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
  • a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
  • the compounds of the formula I in combination with PPAR alpha agonist e.g. GW 9578, GW 7647.
  • the compounds of the formula I are used in combination with a mixed PPAR alpha / gamma agonist, e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 11833, PCT / US 11490, DE10142734.4.
  • a mixed PPAR alpha / gamma agonist e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 11833, PCT / US 11490, DE10142734.4.
  • the compounds of the formula I in combination with a fibrate such as e.g. Fenofibrate, clofibrate, bezafibrate.
  • the compounds of the formula I in Combination with an MTP inhibitor such as Implitapide, BMS-201038, R-103757, administered.
  • the compounds of the formula I are used in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221, 897), such as e.g. HMR 1741.
  • the compounds of the formula I in combination with a CETP inhibitor such as e.g. JTT-705.
  • the compounds of the formula I are used in combination with a polymeric bile acid adsorber, such as e.g. Cholestyramine, Colesevelam administered.
  • a polymeric bile acid adsorber such as e.g. Cholestyramine, Colesevelam administered.
  • the compounds of the formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMR1171, HMR1586.
  • the compounds of the formula I in combination with an ACAT inhibitor such as e.g. Avasimibe administered.
  • the compounds of the formula I in combination with an antioxidant, such as e.g. OPC-14117.
  • the compounds of the formula I in combination with a lipoprotein lipase inhibitor, such as e.g. NO-1886.
  • the compounds of the formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990.
  • the compounds of the formula I in combination with a squalene synthetase inhibitor such as, for example, BMS-188494, administered.
  • the compounds of the formula I are antagonized in combination with a lipoprotein (a), e.g. CI-1027 or nicqtic acid.
  • a lipoprotein
  • the compounds of the formula I in combination with a lipase inhibitor, such as e.g. Orlistat administered.
  • a lipase inhibitor such as e.g. Orlistat administered.
  • the compounds of formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.
  • a sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.
  • the compounds of formula 1 in combination with a biguanide, e.g. Metformin.
  • the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.
  • a meglitinide such as, for example, repaglinide.
  • the compounds of the formula I are used in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr.
  • the compounds of formula I are administered in combination with a ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose
  • a ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose
  • the compounds of formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compounds of the formula I are used in combination with more than one of the abovementioned compounds, for example in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, Repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. are administered.
  • the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M .: Hormone and Metabolie Research (2001), 33 (9), 554-558), NPY antagonists e.g. Naphthalene-1 -sulfonic acid- ⁇ 4 - [(4-amino-quinazolin-2-ylamino) methyl] -cyclohexylmethyl ⁇ -amide hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1, 2,3 , 4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo
  • CRF BP antagonists e.g. urocortin
  • urocortin agonists e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl -1 H-indol-6-yloxy) ethylaminoj-ethanol hydrochloride (WO 01/83451)
  • MSH melanocyte-stimulating hormone
  • CCK-A agonists e.g.
  • Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase Inhibitors (eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR modulators or TR-? Agonists are administered.
  • DA agonists bromocriptine, doprexin
  • lipase / amylase Inhibitors eg WO 00/40569
  • PPAR modulators eg WO 00/78312
  • RXR modulators or TR-? Agonists are administered.
  • the further active ingredient is leptin; see e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gonnez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
  • the further active ingredient is dexamphatamine or
  • the further active ingredient is fenfluramine or dexfenfluramine.
  • the further active ingredient is sibutramine.
  • the further active ingredient is orlistat. In one embodiment, the further active ingredient is mazindol or phentermine.
  • the compounds of formula I in combination with bulking agents preferably insoluble bulking agents
  • bulking agents preferably insoluble bulking agents
  • Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)).
  • the combination with Caromax ® can be done in one preparation or by separate administration of compounds of formula I and Caromax ® .
  • Caromax ® can also be administered in the form of food, such as in baked goods or granola bars.
  • JTT-501 The examples listed below serve to illustrate the invention, but without restricting it.
  • test substances were prepared as a 10 mM solution in DMSO and diluted to 50 ⁇ M with buffer solution T. 10 ⁇ l of this solution were mixed with 10 ⁇ l of 37.5 mM glucose, dissolved in buffer solution T and 5 mg / ml glycogen, and 10 ⁇ l of a solution of human glycogen phosphorylase a (10 ⁇ g
  • Comparative Example A shows no inhibition at a concentration of 10 ⁇ M and 11% inhibition at a concentration of 100 ⁇ M. It can be seen from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are therefore very suitable for lowering the blood sugar level. In particular, the compounds of the formula I have a markedly increased activity compared to comparative example A.
  • the crude product was purified by preparative HPLC (column: Waters Xterra TM MS C 18 , 5 ⁇ m, 30x100 mm, eluent: A: H 2 0 + 0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A / 10% B to 17.5 minutes 10% A / 90% B) cleaned. 0.03 g of the desired product was obtained. Melting point 225-228 ° C
  • Examples 2-8, 27-62 and 78-88 were prepared from the corresponding nitroanilines and the corresponding isocyanates, if necessary using customary protecting group techniques.
  • Examples 65 to 70 were prepared analogously, using other acylating agents as in Example 1d.
  • Citric acid solution (10%) adjusted to pH 4 and washed four times with water.
  • Examples 71, 72 and 74-77 were prepared from the corresponding amines and the respective acylating agents, if appropriate using conventional protecting group techniques.
  • Example 19-26 and 63 4-amino-3-methoxybenzoic acid was nitrated with urea nitrate analogously to Example 64a. The subsequent synthetic route was the same as that shown in Example 1.
  • N- (4-methoxy-2-methylphenyl) acetamide or N- (2-methoxy-4-methylphenyl) acetamide were nitrated under normal conditions (HN0 3 / HOAc), the amide with conc. Cleaved hydrochloric acid (analogously to Example 73c) and reacted further as described for Example 1.

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Abstract

The invention relates to compounds of formula (I) wherein the radicals have the cited meaning, in addition to the physiologically compatible salts thereof. The compounds, for example, can be used as medicaments for preventing and treating type 2 diabetes.

Description

Beschreibungdescription
Carbonylamino-substituierte Acyl-phenyl-harnstoffderivate, Verfahren zu deren Herstellung und deren VerwendungCarbonylamino-substituted acyl-phenyl-urea derivatives, process for their preparation and their use
Die Erfindung betrifft Carbonylamino-substituierte Acyl-phenyl-harnstoffderivate sowie deren physiologisch verträgliche Salze und physiologisch funktionelle Derivate.The invention relates to carbonylamino-substituted acyl-phenyl-urea derivatives and their physiologically tolerable salts and physiologically functional derivatives.
In WO 9946236 (Novo Nordisk) werden Carbonylamino-substituierte Acyl-phenyl- hamstoffderivate (Beispiel 1 ) mit Wirkung bei Typ 2 Diabetes beschrieben.WO 9946236 (Novo Nordisk) describes carbonylamino-substituted acylphenylurea derivatives (example 1) with action in type 2 diabetes.
In WO 00/07991 (PCT/GB99/02489 Astra Zeneca) werden Amidderivate als Inhibitoren der Bildung von Cytokinen beschrieben.WO 00/07991 (PCT / GB99 / 02489 Astra Zeneca) describes amide derivatives as inhibitors of the formation of cytokines.
Der Erfindung lag die Aufgabe zugrunde, Verbindungen zur Verfügung zu stellen, mit denen eine Prävention und Behandlung von Diabetes Typ II möglich ist. Die Verbindungen sollten dazu insbesondere eine therapeutisch verwertbare Blutzucker senkende Wirkung entfalten.The invention had for its object to provide compounds with which prevention and treatment of type II diabetes is possible. For this purpose, the compounds should in particular have a therapeutically utilizable blood sugar-lowering effect.
Die Erfindung betrifft daher Verbindungen der Formel I,The invention therefore relates to compounds of the formula I
R4R4
R10 R11R10 R11
worin bedeuten R8, R9, R10, R11 unabhängig von einander H, F, Cl, Br, OH, N02, CN, 0-(Cin what mean R8, R9, R10, R11 independently of one another H, F, Cl, Br, OH, N0 2 , CN, 0- (C
C5)-Alkyl, 0-(C2-C6)-Alkenyl, 0-(C2-C6)-Alkinyl, 0-S02-(d-C4)-Alkyl, (d- C6)-Alkyl, (C2-C6)-Alkenyl oder (C2-C6)-Alkinyl, wobei Alkyl, Alkenyl und Alkinyl mehrfach durch F, Cl oder Br substituiert sein können;C 5 ) alkyl, 0- (C 2 -C 6 ) alkenyl, 0- (C 2 -C 6 ) alkynyl, 0-S0 2 - (dC 4 ) alkyl, (d- C 6 ) alkyl , (C 2 -C 6 ) alkenyl or (C 2 -C 6 ) alkynyl, where alkyl, alkenyl and alkynyl can be substituted several times by F, Cl or Br;
R1 , R2 unabhängig voneinander H, (Cι-C6)-Alkyl, wobei Alkyl mit OH, 0-(d-C4)-R1, R2 independently of one another are H, (-CC 6 ) -alkyl, alkyl having OH, 0- (dC 4 ) -
Alkyl, NH2) NH(Cι-C4)-Alkyl, N[(C C6)-Alkyl]2 substituiert sein kann, O- (d-C6)-Alkyl, CO-(CrC6)-Alkyl, COO-(Cι-C6)-Alkyl, (d-C6)-A!kylen- COOH oder (d-C6)-Alkylen-COO-(d-C6)-alkyl;Alkyl, NH 2) NH (-CC 4 ) -alkyl, N [(CC 6 ) -alkyl] 2 can be substituted, O- (dC 6 ) -alkyl, CO- (CrC 6 ) -alkyl, COO- ( -CC 6 ) alkyl, (dC 6 ) -A! Kylene-COOH or (dC 6 ) -alkylene-COO- (dC 6 ) -alkyl;
R3, R4, R5, R6 unabhängig voneinander H, F, Cl, Br, N02, CN, 0-R12, O-R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, O-
Phenyl, S-R12, COOR12, N(R13)(R14), (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(C1-C4)-alkylen oder 0-(CrC5)-Alkyl-COOR12, wobei Alkyl, Cycloalkyl, Alkylen und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12 oder N(R13)(R14) substituiert sein können;Phenyl, S-R12, COOR12, N (R13) (R14), (dC 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 ) -Cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (C 1 -C 4 ) -alkylene or 0- (CrC 5 ) -alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl are used several times with F, Cl, Br, OR12, COOR12 or N (R13) (R14) may be substituted;
R7 H, (d-C6)-Alkyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(Cι-C4)-alkylen,R7 H, (dC 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (-C-C 4 ) -alkylene,
(C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (CrC6)-Alkylcarboxy-(Cι-C6)-alkylen, COOR12, (C6-C10)-Aryl, (C6-Cι0)-Aryl-(C1-C )-alkylen, Heterocyclischer(C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (CrC 6 ) alkylcarboxy- (-C-C 6 ) alkylene, COOR12, (C 6 -C 10 ) aryl, (C 6 -Cι 0 ) aryl (C 1 -C) alkylene, heterocyclic
Rest, Heteroaryl-(d-C )-alkylen oder Heteroarylcarbonyl, wobei Alkyl, Cycloalkyl, Alkylen, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12, CONH2, CONH(C1-C6)-Alkyl, CON[(d-C6)-Alkyl]2 oder N(R13)(R14) substituiert sein können und wobei Aryl und Heteroaryl mehrfach mit F, Cl, Br, N02, CN, 0-R12, S-R12, COOR12, N(R13)(R14), oder (CrC6)-Alkyl substituiert sein können;Radical, heteroaryl- (dC) -alkylene or heteroarylcarbonyl, alkyl, cycloalkyl, alkylene, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OR12, COOR12, CONH 2 , CONH (C 1 -C 6 ) -alkyl, CON [ (dC 6 ) -alkyl] 2 or N (R13) (R14) can be substituted and where aryl and heteroaryl are used several times with F, Cl, Br, NO 2 , CN, 0-R12, S-R12, COOR12, N (R13 ) (R14), or (CrC 6 ) alkyl may be substituted;
R12 H, (Cι-C8)-Alkyl, (C2-C8)-Alkenyl oder (C2-C8)-Alkinyl, wobei Alkyl, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OH oder 0-(Cι-C4)-Alkyl substituiert sein können,R12 H, (-CC 8 ) -alkyl, (C 2 -C 8 ) -alkenyl or (C 2 -C 8 ) -alkynyl, alkyl, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OH or 0- (C 1 -C 4 ) -alkyl can be substituted,
R13, R14 unabhängig voneinander H, (d-C8)-Alkyl, (C2-C8)-Alkenyl, (C2-C8)-Alkinyl, (C3-C7)-Cycioalkyl, (C3-C7)-Cyc.oa.kyKCrC4)-alkylen, COO-(CrC4)-Alkyl, COO-^-C-^-Alkenyl, Phenyl oder S02-Phenyl, wobei der Phenylring bis zu zweifach mit F, Cl, CN, OH, (d-C6)-Alkyl, O-td-CeJ-Alkyl, CF3, OCF3, COOH, COO(d-C6)-Alkyl oder CONH2 substituiert sein kann; wobei R13 und R14 gemeinsam mit dem Stickstoffatom an das sie gebunden sind einen 3-7 gliedrigen, gesättigten heterozyklischen Ring bilden können, der bis zu 2 weitere Heteroatome aus der Gruppe N, O oder S enthalten kann, wobei der heterocyclische Ring bis zu dreifach mit F, Cl, Br, OH, Oxo, N(R21 )(R22) oder (d-C4)-Aikyl substituiert sein kann;R13, R14 independently of one another are H, (dC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) -Cycioalkyl, (C 3 -C 7 ) -Cyc.oa.kyKCrC 4 ) alkylene, COO- (CrC 4 ) alkyl, COO - ^ - C - ^ - alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (dC 6 ) alkyl, O-td-CeJ-alkyl, CF 3 , OCF 3 , COOH, COO (dC 6 ) alkyl or CONH 2 can be substituted; where R13 and R14 together with the nitrogen atom to which they are attached can form a 3-7 membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, the heterocyclic ring having up to three times with F, Cl, Br, OH, Oxo, N (R21) (R22) or (dC 4 ) -alkyl can be substituted;
R21 , R22 unabhängig voneinander H, (Cι-C8)-Alkyl, (C -C8)-Alkenyl, (C2-C8)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(C C4)-alkylen, COO-(d-C4)-Alkyl, COO-(C2-C4)-Alkenyl, Pheny! oder S02-Phenyl, wobei der Phenylring bis zu zweifach mit F, Cl, CN, OH, (C C6)-Alkyl, 0-(C1-C6)-Alkyl, CF3, OCF3> COOH, COO(d-C6)-Alkyl oder CONH2 substituiert sein kann;R21, R22 independently of one another H, (-CC 8 ) alkyl, (C -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (CC 4 ) -alkylene, COO- (dC 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, pheny! or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (CC 6 ) -alkyl, 0- (C 1 -C 6 ) -alkyl, CF 3 , OCF 3> COOH, COO ( dC 6 ) alkyl or CONH 2 may be substituted;
wobei Verbindungen der Formel 1 ausgenommen sind, in denen die Reste gleichzeitig die folgenden Bedeutung haben:with the exception of compounds of the formula 1 in which the radicals simultaneously have the following meaning:
R5 gleich Halogen oder unsubstituiertes (d-C6)-Alkyl, R7 gleich Heterocyclischer Rest oder Heteroaryl;R5 is halogen or unsubstituted (dC 6 ) alkyl, R7 is heterocyclic radical or heteroaryl;
sowie deren physiologisch verträgliche Salze.and their physiologically tolerable salts.
Bevorzugt sind Verbindungen der Formel I worin ein oder mehrere Reste folgende Bedeutung haben:Compounds of the formula I in which one or more radicals have the following meaning are preferred:
R8, R9, R10, R11 unabhängig von einander H, F, Cl, Br, OH, N02, CN, 0-(C C6)-Alkyl, wobei Alkyl mehrfach durch F, Cl oder Br substituiert sein kann;R8, R9, R10, R11 independently of one another H, F, Cl, Br, OH, NO 2 , CN, 0- (CC 6 ) -alkyl, where alkyl can be substituted several times by F, Cl or Br;
R , R2 H; R3, R4, R5, R6 unabhängig voneinander H, F, Cl, Br, N02, CN, 0-R12, O-R, R2 H; R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, O-
Phenyl, S-R12, COOR12, N(R13)(R14), (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(C C4)-alkylen oder 0-(Cι-C5)-Alkyl-COOR12, wobei Alkyl, Cycloalkyl, Alkylen und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12 oder N(R13)(R14), substituiert sein können;Phenyl, S-R12, COOR12, N (R13) (R14), (dC 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 ) -Cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (CC 4 ) -alkylene or 0- (-C-C 5 ) -alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl several times with F, Cl, Br, OR12 , COOR12 or N (R13) (R14), may be substituted;
R7 H, (C C6)-Alkyl, (C3-C7)-Cycloalkyl, (C2-C6)-Aikenyl, (C2-C6)-Alkiny!, (d- C6)-Alkylcarboxy-(CrC6)-alkylen, COOR12, (C6-C10)-Aryl, (C6-C10)-Aryl-R7 H, (CC 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) aikenyl, (C 2 -C 6 ) alkynyl !, (d- C 6 ) alkylcarboxy- (CrC 6 ) alkylene, COOR12, (C 6 -C 10 ) aryl, (C 6 -C 10 ) aryl
(Cι-C )-alkylen, Heteroaryl, Heteroaryl-(d-C4)-alkylen oder(-C-C) alkylene, heteroaryl, heteroaryl (dC 4 ) alkylene or
Heteroarylcarbonyl, wobei . Alkyl, Cycloalkyl, Alkylen, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12, CONH2, CONH(d-C6)-Alkyl, CON[(CrC6)-Alkyl]2 oder N(R13)(R14) substituiert sein können und wobei Aryl und Heteroaryl mehrfach mit F, Cl, Br, N02, CN, 0-R12, S-R12,Heteroarylcarbonyl, wherein . Alkyl, cycloalkyl, alkylene, alkenyl and alkynyl several times with F, Cl, Br, OR12, COOR12, CONH 2 , CONH (dC 6 ) -alkyl, CON [(CrC 6 ) -alkyl] 2 or N (R13) (R14) may be substituted and wherein aryl and heteroaryl are repeatedly substituted with F, Cl, Br, N0 2 , CN, 0-R12, S-R12,
COOR12, N(R13)(R14), oder (d-C6)-Alkyl substituiert sein können;COOR12, N (R13) (R14), or (dC 6 ) alkyl may be substituted;
R12 H, (Cι-Cβ)-Alkyl, (C2-C8)-Alkenyl oder (C2-C8)-Alkinyl, wobei Alkyl, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OH oder 0-(d-C4)-Alkyl substituiert sein können,R12 H, (-C-Cβ) alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 ) alkynyl, alkyl, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OH or 0- ( dC 4 ) -alkyl may be substituted,
R13, R14 unabhängig voneinander H, (Cι-C8)-Alkyl, (C2-C8)-Alkenyl, (C2-C8)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(C C4)-alkylen, COO-(d-C4)-Alkyl, COO-(C2-C4)-Alkenyl, Phenyl oder S02-Phenyl, wobei der Phenylring bis zu zweifach mit F, Cl, CN, OH, (d-C6)-Alkyl, 0-(C C6)-Alkyl, CF3, OCF3,R13, R14 independently of one another H, (-CC 8 ) -alkyl, (C 2 -C 8 ) -alkenyl, (C 2 -C 8 ) -alkynyl, (C 3 -C 7 ) -cycloalkyl, (C 3 - C 7 ) -cycloalkyl- (CC 4 ) -alkylene, COO- (dC 4 ) -alkyl, COO- (C 2 -C 4 ) -alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (dC 6 ) alkyl, 0- (CC 6 ) alkyl, CF 3 , OCF 3 ,
COOH, COO(C C6)-Alkyl oder CONH2 substituiert sein kann; wobei R13 und R14 gemeinsam mit dem Stickstoffatom an das sie gebunden sind einen 3-7 gliedrigen, gesättigten heterozyklischen Ring bilden können, der bis zu 2 weitere Heteroatome aus der Gruppe N, O oder S enthalten kann, wobei der heterocyclische Ring bis zu dreifach mit F, Cl, Br, OH,COOH, COO (CC 6 ) alkyl or CONH 2 may be substituted; where R13 and R14 together with the nitrogen atom to which they are attached can form a 3-7 membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, the heterocyclic ring having up to three times with F, Cl, Br, OH,
Oxo, N(R21 )(R22) oder (C C4)-Alkyl substituiert sein kann; R21 , R22 unabhängig voneinander H, (d-C8)-Alkyl;Oxo, N (R21) (R22) or (CC 4 ) alkyl may be substituted; R21, R22 independently of one another are H, (dC 8 ) -alkyl;
wobei Verbindungen der Formel I ausgenommen sind, in denen die Reste gleichzeitig die folgenden Bedeutung haben: "R5 gleich Halogen oder unsubstituiertes (d-C6)-Alkyl, R7 gleich Heterocyclischer Rest oder Heteroaryl;with the exception of compounds of the formula I in which the radicals simultaneously have the following meaning: " R5 is halogen or unsubstituted (dC 6 ) alkyl, R7 is heterocyclic radical or heteroaryl;
sowie deren physiologisch verträgliche Salze.and their physiologically tolerable salts.
Besonders bevorzugt sind Verbindungen der Formel I worin ein oder mehrere Reste folgende Bedeutung haben:Compounds of the formula I in which one or more radicals have the following meaning are particularly preferred:
R8, R9, R10, R11 unabhängig von einander H, F oder Cl;R8, R9, R10, R11 independently of one another H, F or Cl;
R1 , R2, R4, R6 H;R1, R2, R4, R6 H;
R3, R5 unabhängig voneinander H, Cl, OR12, COOR12, N(R13)(R14) oder (d-R3, R5 independently of one another H, Cl, OR12, COOR12, N (R13) (R14) or (d-
C6)-Alkyl;C 6 ) alkyl;
R7 (d-C6)-Alkyl, wobei Alkyl mehrfach mit F, OR12, COOR12 oderR7 (dC 6 ) -alkyl, where alkyl is repeated with F, OR12, COOR12 or
N(R13)(R14) substituiert sein kann, (C3-C6)-Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C1-C5)-Alkylcarboxy-(C1-C6)-alkyIen, COOR12, Phenyl, wobei Phenyl mehrfach mit F, OMe oder OCF3 substituiert sein kann, Benzyl, wobei dessen Phenylring mit OMe substituiert sein kann, Pyridyl,N (R13) (R14) may be substituted, (C 3 -C 6 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 5 ) alkylcarboxy - (C 1 -C 6 ) -alkylene, COOR12, phenyl, where phenyl can be substituted several times with F, OMe or OCF 3 , benzyl, where the phenyl ring can be substituted with OMe, pyridyl,
Thienyl, Furanyl, Indolylcarbonyl, Benzofuranyl, wobei Benzofuranyl mit Cl oder OMe substituiert sein kann;Thienyl, furanyl, indolylcarbonyl, benzofuranyl, where benzofuranyl can be substituted with Cl or OMe;
R12 H oder (d-Cs)-Alkyl, wobei Alkyl mehrfach mit F substituiert sein kann;R12 is H or (d-Cs) -alkyl, where alkyl can be substituted several times by F;
R13, R14 unabhängig voneinander H oder (C-rC8)-Alkyl; und wobei R13 und R14 gemeinsam mit dem Stickstoffatom an das sie gebunden sind einen 5- gliedrigen, gesättigten heterocyclischen Ring bilden können;R13, R14 independently of one another are H or (C-rC 8 ) -alkyl; and where R13 and R14 together with the nitrogen atom to which they are attached can form a 5-membered, saturated heterocyclic ring;
wobei Verbindungen der Formel I ausgenommen sind, in denen die Reste gleichzeitig die folgenden Bedeutung haben: R5 gleich Halogen oder unsubstituiertes (d-C6)-Alkyl, R7 gleich Heterocyclischer Rest oder Heteroaryl;with the exception of compounds of the formula I in which the radicals simultaneously have the following meaning: R5 is halogen or unsubstituted (dC 6 ) alkyl, R7 is heterocyclic radical or heteroaryl;
sowie deren physiologisch verträgliche Salze.and their physiologically tolerable salts.
Die Erfindung bezieht sich auf Verbindungen der Formel I, in Form ihrer Racemate, racemischen Mischungen und reinen Enantiomere sowie auf ihre Diastereomere und Mischungen davon.The invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
Die Alkylreste in den Substituenten R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 R12, R13, R14, R21 und R22 können sowohl geradkettig wie verzweigt sein.The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 R12, R13, R14, R21 and R22 can be either straight-chain or branched.
Können Reste oder Substituenten mehrfach in den Verbindungen der Formel I auftreten, wie zum Beispiel 0-R12, so können sie alle unabhängig voneinander die angegebenen Bedeutungen haben und gleich oder verschieden sein.If radicals or substituents can occur more than once in the compounds of the formula I, for example 0-R12, they can all independently of one another have the meanings given and be the same or different.
Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche Säureadditionssalze der erfindungsgemäßen Verbindungen sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor-, Metaphosphor-, Salpeter- und Schwefelsäure sowie organischer Säuren, wie z.B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isethion-, Milch-, Lactobion-, Malein-, Äpfel-, Methansulfon-, Bernstein-, p-Toluolsulfon- und Weinsäure. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, AI- kalimetallsalze (wie Natrium- und Kaliumsalze), Erdalkalisalze (wie Magnesium- und Calciumsalze), Trometamol (2-Amino-2-hydroxymethyl-1 ,3-propandiol), Diethanolamin, Lysin, oder Ethylendiamin.Pharmaceutically acceptable salts are particularly suitable for medical applications due to their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric , Gluconic, glycolic, isethione, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, Al- potassium metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine, or ethylenediamine.
Salze mit einem nicht pharmazeutisch verträglichen Anion, wie zum Beispiel Trifluoracetat, gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nicht-therapeutischen, zum Beispiel in-vitro- Anwendungen.Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in vitro, applications.
Der hier verwendete Begriff "physiologisch funktionelles Derivat" bezeichnet jedes physiologisch verträgliche Derivat einer erfindungsgemäßen Verbindung der Formel I, z.B. einen Ester, der bei Verabreichung an einen Säuger, wie z.B. den Menschen, in der Lage ist, (direkt oder indirekt) eine Verbindung der Formel I oder einen aktiven Metaboliten hiervon zu bilden.The term "physiologically functional derivative" as used herein denotes any physiologically compatible derivative of a compound of formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able (directly or indirectly) to form a compound of formula I or an active metabolite thereof.
Zu den physiologisch funktionellen Derivaten zählen auch Prodrugs der erfindungsgemäßen Verbindungen, wie zum Beispiel in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61 beschrieben. Solche Prodrugs können in vivo zu einer erfindungsgemäßen Verbindung metabolisiert werden. Diese Prodrugs können selbst wirksam sein oder nicht.The physiologically functional derivatives also include prodrugs of the compounds according to the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may or may not work themselves.
Die erfindungsgemäßen Verbindungen können auch in verschiedenen polymorphen Formen vorliegen, z.B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der erfindungsgemäßen Verbindungen gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung.The compounds of the invention can also exist in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong to the scope of the invention and are a further aspect of the invention.
Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel I" auf Verbindung(en) der Formel I wie vorstehend beschrieben, sowie ihre Salze, Solvate und physiologisch funktioneilen Derivate wie hierin beschrieben. Unter einem Arylrest wird ein Phenyl-, Naphthyl-, Biphenyl-, Tetrahydronaphthyl-, alpha- oder beta-Tetralon-, Indanyl- oder lndan-1-on-ylrest verstanden.In the following, all references to "compound (s) according to formula I" refer to compound (s) of formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein. An aryl radical is understood to mean a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralone, indanyl or indan-1-one-yl radical.
Die hier verwendeten Begriffe "Heterocyclischer Ring" bzw. "Heterocyclischer Rest" beziehen sich auf Heteroarylreste und Heterocycloalkylrerste, die sich aus 3 bis 10 glieddrigen Kohlenstoffringen ableiten, in denen ein oder mehrere Kohlenstoffatome durch ein oder mehrere Atome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff, ersetzt sind.The terms "heterocyclic ring" and "heterocyclic radical" used here refer to heteroaryl radicals and heterocycloalkyl radicals which are derived from 3 to 10-membered carbon rings in which one or more carbon atoms are selected from the group oxygen, sulfur and one or more atoms and nitrogen.
Geeignete "Heterocyclische Ringe" bzw. "Heterocyclischer Reste" sind Acridinyl, Azocinyl, Benzimidazolyl, Benzofuryl, Benzothienyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Benzimidazalinyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H- Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Decahydrochinolinyl, 2H,6H-1 ,5,2-Dithiazinyl, Dihydrofuro[2,3-b]-Tetrahydrofuran, Furyl, Furazanyl, lmidazolidinyl, Imidazolinyl, lmidazolyl, 1 H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolyl, Isoxazolyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5-Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pyridooxazole, Pyridoimidazole, Pyridothiazole, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, 6H-1.2,5-Thiadazinyl, Thiazolyl, 1 ,2,3-Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5- Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thienyl, Triazolyl, Tetrazolyl und Xanthenyl.Suitable “heterocyclic rings” or “heterocyclic radicals” are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazidazolinyl, carbazidazolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5,2-dithiazinyl, dihydrofuro [2,3-b] -tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, lmid H-lndazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, P henoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, Purynyl, pyranyl, pyrazinyl, Pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, Pyridooxazole, pyridoimidazoles, Pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, Tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thienyl, triazolyl, Tetrazolyl and xanthenyl.
Pyridyl steht sowohl für 2-, 3- als auch 4-Pyridyl. Thienyl steht sowohl für 2- als auch 3- Thienyl. Furyl steht sowohl für 2- als auch 3-Furyl.Pyridyl represents both 2-, 3- and 4-pyridyl. Thienyl represents both 2- and 3- thienyl. Furyl stands for both 2- and 3-furyl.
Umfasst sind weiterhin die entsprechenden N-Oxide dieser Verbindungen, also z.B. 1- Oxy-2-, 3- oder 4-pyridyl.The corresponding N-oxides of these compounds, for example 1- Oxy-2-, 3- or 4-pyridyl.
Umfasst sind weiterhin ein oder mehrfach benzoannelierte Derivate dieser Heterozykien.One or more benzo-fused derivatives of these heterocycles are also included.
Die Verbindung(en) der Formel (I) können auch in Kombination mit weiteren Wirkstoff verabreicht werden.The compound (s) of the formula (I) can also be administered in combination with other active ingredients.
Die Menge einer Verbindung gemäß Formel I, die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z.B. der gewählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art der Verabreichung und dem klinischen Zustand des Patienten. Im allgemeinen liegt die Tagesdosis im Bereich von 0,3 mg bis 100 mg (typischerweise von 3 mg und 50 mg) pro Tag pro Kilogramm Körpergewicht, z.B. 3-10 mg/kg/Tag. Eine intravenöse Dosis kann z.B. im Bereich von 0,3 mg bis 1 ,0 mg/kg liegen, die geeigneterweise als Infusion von 10 ng bis 100 ng pro Kilogramm pro Minute verabreicht werden kann. Geeignete Infusionslösungen für diese Zwecke können z.B. von 0,1 ng bis 10 mg, typischerweise von 1 ng bis 10 mg pro Milliliter, enthalten. Einzeldosen können z.B. von 1 mg bis 10 g des Wirkstoffs enthalten. Somit können Am- pullen für Injektionen beispielsweise von 1 mg bis 100 mg, und oral verabreichbare Einzeldosisformulierungen, wie zum Beispiel Tabletten oder Kapseln, können beispielsweise von 1 ,0 bis 1000 mg, typischerweise von 10 bis 600 mg enthalten. Zur Therapie der oben genannten Zustände können die Verbindungen gemäß Formel I selbst als Verbindung verwendet werden, vorzugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muss natürlich verträglich sein, in dem Sinne, dass er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheitsschädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel I. Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im wesentlichen darin bestehen, dass die Bestandteile mit pharmakologisch verträglichen Träger- und/oder Hilfsstoffen - gemischt werden.The amount of a compound of formula I required to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day per kilogram of body weight, for example 3-10 mg / kg / day. An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg / kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes can contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses can contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections can contain, for example, from 1 mg to 100 mg, and orally administrable single-dose formulations, such as tablets or capsules, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the abovementioned conditions, the compounds of the formula I themselves can be used as a compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier. The carrier must of course be compatible, in the sense that it is compatible with the other components of the composition and is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances can also be present, including further compounds according to formula I. The invention Pharmaceutical compositions can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the components with pharmacologically acceptable carriers and / or auxiliaries.
Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale, rektale, topische, perorale (z.B. sublinguale) und parenterale (z.B. subkutane, intramuskuläre, intradermale oder intravenöse) Verabreichung geeignet sind, wenngleich die geeignetste Verabreichungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel I abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Poylvinylacetatphthalat, Hydroxypropyimethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case depends on the type and severity of the to be treated State and on the type of compound used according to formula I is dependent. Coated formulations and coated slow-release formulations also fall within the scope of the invention. Formulations which are resistant to acid and gastric juice are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tabletten, die jeweils eine bestimmte Menge der Verbindung • gemäß Formel I enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wässrigen oder nicht-wässrigen Flüssigkeit; oder als eine Öl-in-Wasser- oder Wasser-in-ÖI-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfasst, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allgemeinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpresst oder geformt wird, gegebenenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepresste Tabletten können durch tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdünner und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.Suitable pharmaceutical compounds for oral administration can be present in separate units, such as capsules, capsules, lozenges or tablets, each containing a certain amount of the compound • according to formula I; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared by any suitable pharmaceutical method comprising a step in which the active ingredient and the carrier (which can consist of one or more additional ingredients) are brought into contact. In general, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary. For example, a tablet can be produced by compressing or molding a powder or granulate of the compound, optionally with one or more additional components. Pressed tablets can be compressed into tablets Compound in free flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (more) surface-active / dispersing agent in a suitable machine. Molded tablets can be made by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.
Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung geeignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel I mit einem Geschmacksstoff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oder Saccharose und Gummi arabicum umfassen.Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and gum arabic.
Geeignete pharmazeutische Zusammensetzungen für die parenterale Verabreichung umfassen vorzugsweise sterile wässrige Zubereitungen einer Verbindung gemäß Formel I, die vorzugsweise isotonisch mit dem Blut des vorgesehenen Empfängers sind. Diese Zubereitungen werden vorzugsweise intravenös verabreicht, wenngleich die Verabreichung auch subkutan, intramuskulär oder intradermal als Injektion erfolgen kann. Diese Zubereitungen können vorzugsweise hergestellt werden, indem die Verbindung mit Wasser gemischt wird und die erhaltene Lösung steril und mit dem Blut isotonisch gemacht wird. Injizierbare erfindungsgemäße Zusammensetzungen enthalten im allgemeinen von 0,1 bis 5 Gew.-% der aktiven Verbindung.Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they can also be administered subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be prepared by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Geeignete pharmazeutische Zusammensetzungen für die rektale Verabreichung liegen vorzugsweise als Einzeldosis-Zäpfchen vor. Diese können hergestellt werden, indem man eine Verbindung gemäß Formel I mit einem oder mehreren herkömmlichen festen Trägern, beispielsweise Kakaobutter, mischt und das entstehende Gemisch in Form bringt.Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be prepared by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Geeignete pharmazeutische Zusammensetzungen für die topische Anwendung auf der Haut liegen vorzugsweise als Salbe, Creme, Lotion, Paste, Spray, Aerosol oder Öl vor. Als Träger können Vaseline, Lanolin, Polyethylenglykole, Alkohole und Kombinationen von zwei oder mehreren dieser Substanzen verwendet werden. Der Wirkstoff. ist im allgemeinen in einer Konzentration von 0,1 bis 15 Gew.-% der Zusammensetzung vorhanden, beispielsweise von 0,5 bis 2%.Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols and combinations can be used as carriers can be used by two or more of these substances. The active substance. is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.
Auch eine transdermale Verabreichung ist möglich. Geeignete pharmazeutische Zusammensetzungen für transdermale Anwendungen können als einzelne Pflaster vorliegen, die für einen langzeitigen engen Kontakt mit der Epidermis des Patienten geeignet sind. Solche Pflaster enthalten geeigneterweise den Wirkstoff in einer gegebenenfalls gepufferten wässrigen Lösung, gelöst und/oder dispergiert in einem Haftmittel oder dispergiert in einem Polymer. Eine geeignete Wirkstoff-Konzentration beträgt ca. 1 % bis 35%, vorzugsweise ca. 3% bis 15%. Als eine besondere Möglichkeit kann der Wirkstoff, wie beispielsweise in Pharmaceutical Research, 2(6): 318 (1986) beschrieben, durch Elektrotransport oder lontophorese freigesetzt werden.Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications can be presented as individual patches which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is approximately 1% to 35%, preferably approximately 3% to 15%. As a special possibility, the active ingredient can be released by electrotransport or iontophoresis, as described for example in Pharmaceutical Research, 2 (6): 318 (1986).
Als weitere Wirkstoffe für die Kombinationspräparate sind geeignet:The following are also suitable as active ingredients for the combination preparations:
Alle Antidiabetika, die in der Roten Liste 2001 , Kapitel 12 genannt sind. Sie können mit den erfindungsgemäßen Verbindungen der Formel I insbesondere zur synergistischen Wirkungsverbesserung kombiniert werden. Die Verabreichung der Wirkstoffkombination kann entweder durch getrennte Gabe der Wirkstoffe an den Patienten oder in Form von Kombinationspräparaten, worin mehrere Wirkstoffe in einer pharmazeutischen Zubereitung vorliegen, erfolgen. Die meisten der nachfolgend aufgeführten Wirkstoffe sind in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001 , offenbart. Antidiabetika umfassen Insulin und Insulinderivate, wie z.B. Lantus® (siehe www.lantus.com) oder HMR 1964, schnell wirkende lnsuline (siehe US 6,221 ,633), GLP-1 -Derivate wie z.B. diejenigen die in WO 98/08871 von Novo Nordisk A/S offenbart wurden, sowie oral wirksame hypoglykämische Wirkstoffe. Die oral wirksamen hypoglykämischen Wirkstoffe umfassen vorzugsweise Sulphonylfharnstoffe, Biguanidine, Meglitinide, Oxadiazolidindione, Thiazolidindione, Glukosidase-Inhibitoren, Glukagon-Antagonisten, GLP-1-Agonisten,All antidiabetic medicinal products mentioned in the 2001 Red List, Chapter 12. They can be combined with the compounds of the formula I according to the invention in particular to improve the synergistic effect. The active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221, 633), GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk A / S have been disclosed, as well as orally active hypoglycemic agents. The orally active hypoglycemic active ingredients preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists,
Kaliumkanalöffner, wie z.B. diejenigen, die in WO 97/26265 und WO 99/03861 von Novo Nordisk A/S offenbart wurden, Insulin-Sensitizer, Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oder Glykogenolyse beteiligt sind, Modulatoren der Glukoseaufnahme, den Fettstoffwechsel verändernde Verbindungen wie antihyperlipidämische Wirkstoffe und antilipidämische Wirkstoffe, Verbindungen, die die Nahrungsmitteleinnahme verringern, PPAR- und PXR-Agonisten und Wirkstoffe, die auf den ATP-abhängigen Kaliumkanal, der Betazellen wirken.Potassium channel openers, such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes, which are involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, compounds which alter the lipid metabolism such as antihyperlipidemic active substances and antilipidemic active substances, compounds which reduce food intake, PPAR and PXR agonists and active substances which are dependent on the ATP Potassium channel, the beta cells act.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem HMGCoA-Reduktase Inhibitor wie Simvastatin, Fluvastatin, Pravastatin, Lovastatin, Atorvastatin, Cerivastatin, Rosuvastatin verabreicht.In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Cholesterinresorptionsinhibitor, wie z.B. Ezetimibe, Tiqueside, Pamaqueside, verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with a cholesterol absorption inhibitor, such as e.g. Ezetimibe, Tiqueside, Pamaqueside.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem PPAR gamma Agonist, wie z.B. Rosiglitazon, Pioglitazon, JTT- 501 , Gl 262570, verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit PPAR alpha Agonist, wie z.B. GW 9578, GW 7647, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem gemischten PPAR alpha/gamma Agonisten, wie z.B. GW 1536, AVE 8042, AVE 8134, AVE 0847, oder wie in PCT/US 11833, PCT/US 11490, DE10142734.4 beschrieben verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with a mixed PPAR alpha / gamma agonist, e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 11833, PCT / US 11490, DE10142734.4.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Fibrat, wie z.B. Fenofibrat, Clofibrat, Bezafibrat, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with a fibrate, such as e.g. Fenofibrate, clofibrate, bezafibrate.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem MTP-Inhibitor, wie z.B. Implitapide , BMS-201038, R-103757, verabreicht.In one embodiment of the invention, the compounds of the formula I in Combination with an MTP inhibitor, such as Implitapide, BMS-201038, R-103757, administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit Gallensäureresorptionsinhibitor (siehe z.B. US 6,245,744 oder US 6,221 ,897), wie z.B. HMR 1741 , verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221, 897), such as e.g. HMR 1741.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem CETP-Inhibitor, wie z.B. JTT-705 , verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with a CETP inhibitor, such as e.g. JTT-705.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem polymeren Gallensäureadsorber, wie z.B. Cholestyramin, Colesevelam, verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with a polymeric bile acid adsorber, such as e.g. Cholestyramine, Colesevelam administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem LDL-Rezeptorinducer (siehe US 6,342,512), wie z.B. HMR1171 , HMR1586, verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMR1171, HMR1586.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem ACAT-Inhibitor, wie z.B. Avasimibe, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with an ACAT inhibitor, such as e.g. Avasimibe administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Antioxidans, wie z.B. OPC-14117, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with an antioxidant, such as e.g. OPC-14117.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipoprotein-Lipase Inhibitor, wie z.B. NO-1886, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with a lipoprotein lipase inhibitor, such as e.g. NO-1886.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem ATP-Citrat-Lyase Inhibitor, wie z.B. SB-204990, verabreicht.In one embodiment of the invention, the compounds of the formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Squalen Synthetase Inhibitor, wie z.B. BMS-188494, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494, administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipoprotein(a) antagonist, wie z.B. CI-1027 oder Nicqtinsäure, verabreicht.In one embodiment of the invention, the compounds of the formula I are antagonized in combination with a lipoprotein (a), e.g. CI-1027 or nicqtic acid.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I in Kombination mit einem Lipase Inhibitor, wie z.B. Orlistat, verabreicht.In one embodiment of the invention, the compounds of the formula I in combination with a lipase inhibitor, such as e.g. Orlistat administered.
Bei einer Ausführungsform der Erfindung werden die Verbindungen der Formel I inIn one embodiment of the invention, the compounds of the formula I in
Kombination mit Insulin verabreicht.Combined with insulin.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Sulphonylharnstoff, wie z.B. Tolbutamid, Glibenclamid, Glipizid oder Glimepirid verabreicht. Bei einer Ausführungsform werden die Verbindungen der Formel 1 in Kombination mit einem Biguanid, wie z.B. Metformin, verabreicht.In one embodiment the compounds of formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered. In one embodiment, the compounds of formula 1 in combination with a biguanide, e.g. Metformin.
Bei wieder einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Meglitinid, wie z.B. Repaglinid, verabreicht. Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Thiazolidindion, wie z.B. Troglitazon, Ciglitazon, Pioglitazon, Rosiglitazon oder den in WO 97/41097 von Dr. Reddy's Research Foundation offenbarten Verbindungen, insbesondere 5-[[4-[(3,4-Dihydro-3-methyl-4-oxo-2-chinazolinylmethoxy]- phenyl]methyl]-2,4-thiazolidindion, verabreicht. Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem σ-Glukosidase-lnhibitor, wie z.B. Miglitol oder Acarbose, verabreicht. Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit einem Wirkstoff verabreicht, der auf den ATP-abhängigen Kaliumkanal der Betazellen wirkt, wie z.B. Tolbutamid, Glibenclamid, Glipizid, Glimepirid oder Repaglinid. Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit mehr als einer der vorstehend genannten Verbindungen, z.B. in Kombination mit einem Sulphonylharnstoff und Metformin, einem Sulphonylharnstoff und Acarbose, Repaglinid und Metformin, Insulin und einem Sulphonylharnstoff, Insulin und Metformin, Insulin und Troglitazon, Insulin und Lovastatin, etc. verabreicht.In another embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide. In one embodiment, the compounds of the formula I are used in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione, in one embodiment the compounds of formula I are administered in combination with a σ-glucosidase inhibitor such as, for example, miglitol or acarbose In one embodiment, the compounds of formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, the compounds of the formula I are used in combination with more than one of the abovementioned compounds, for example in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, Repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. are administered.
Bei einer weiteren Ausführungsform werden die Verbindungen der Formel I in Kombination mit CART-Modulatoren (siehe "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolie Research (2001 ), 33(9), 554-558), NPY-Antagonisten z.B. Naphthalin-1 -sulfonsäure-{4-[(4-amino-quinazolin-2-ylamino)- methyl]-cyclohexylmethyl}-amid Hydrochlorid (CGP 71683A)), MC4-Agonisten (z.B. 1- Amino-1 ,2,3,4-tetrahydro-naphthalin-2-carbonsäure [2-(3a-benzyl-2-methyl-3-oxo-In a further embodiment, the compounds of the formula I are used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormone and Metabolie Research (2001), 33 (9), 554-558), NPY antagonists e.g. Naphthalene-1 -sulfonic acid- {4 - [(4-amino-quinazolin-2-ylamino) methyl] -cyclohexylmethyl} -amide hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1, 2,3 , 4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo
2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chloro-phenyl)-2-oxo-ethyl]- amid; (WO 01/91752)) , Orexin-Antagonisten (z.B. 1-(2-Methyl-benzoxazol-6-yl)-3- [1 ,5]naphthyridin-4-yl-harnstoff Hydrochlorid (SB-334867-A)), H3-Agonisten (3- Cyclohexyl-1 -(4,4-dimethyl-1 ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-propan-1 -on Oxalsäuresalz (WO 00/63208)); TNF-Agonisten, CRF-Antagonisten (z.B. [2-Methyl-9- (2,4,6-trimethyl-phenyl)-9H-1 ,3,9-triaza-fluoren-4-yl]-dipropyl-amin (WO 00/66585)), CRF BP-Antagonisten (z.B. Urocortin), Urocortin-Agonisten, ?3-Agonisten (z.B. 1-(4- Chloro-3-methanesulfonylmethyl-phenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)- ethylaminoj-ethanol Hydrochlorid (WO 01/83451 )), MSH (Melanocyt-stimulierendes Hormon)-Agonisten, CCK-A Agonisten (z.B. {2-[4-(4-Chloro-2',5-dimethoxy-phenyl)-5- (2-cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethyl-indol-1-yl}-essigsäure Trifluoressigsäuresalz (WO 99/15525)), Serotonin-Wiederaufnahme-Inhibitoren (z.B. Dexfenfiuramine), gemischte Sertonin- und noradrenerge Verbindungen (z.B. WO 00/71549), 5HT-Agonisten z.B. 1-(3-Ethyl-benzofuran-7-yl)-piperazin Oxalsäuresalz (WO 01/09111 ), Bombesin-Agonisten, Galanin-Antagonisten, Wachstumshormon (z.B. humanes Wachstumshormon), Wachstumshormon freisetzende Verbindungen (6- Benzyloxy-1-(2-diisopropylamino-ethylcarbamoyl)-3,4-dihydro-1 H-isochinolin-2- carbonsäuretertiärbutylester (WO 01/85695)), TRH-Agonisten (siehe z.B. EP 0 462 884) entkoppelnde Protein 2- oder 3-Modulatoren, Leptinagonisten (siehe z.B. Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881 ), DA-Agonisten (Bromocriptin, Doprexin), Lipase/Amylase- Inhibitoren (z.B. WO 00/40569), PPAR-Modulatoren (z.B. WO 00/78312), RXR- Modulatoren oder TR- ?-Agonisten verabreicht.2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl] amide; (WO 01/91752)), orexin antagonists (e.g. 1- (2-methyl-benzoxazol-6-yl) -3- [1, 5] naphthyridin-4-yl-urea hydrochloride (SB-334867-A)) , H3 agonists (3-cyclohexyl-1 - (4,4-dimethyl-1, 4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) propan-1 -one oxalic acid salt ( WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triaza-fluoren-4-yl] dipropyl amine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,? 3 agonists (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl -1 H-indol-6-yloxy) ethylaminoj-ethanol hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2- [4- (4-chloro- 2 ' , 5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl-indol-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525)), Serotonin reuptake inhibitors (e.g. dexfenfiuramine), mixed sertonine and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1- (3-ethyl-benzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111) , Bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1 H-isoquinoline- 2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see eg EP 0 462 884) decoupling protein 2 or 3 modulators, leptin agonists (see eg Lee, Daniel W .; Leinung, Matthew C; Rozhavskaya Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase Inhibitors (eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR modulators or TR-? Agonists are administered.
Bei einer Ausführungsform der Erfindung ist der weitere Wirkstoff Leptin; siehe z.B. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gonnez- Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001 ), 2(10), 1615-1622.In one embodiment of the invention, the further active ingredient is leptin; see e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gonnez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
Bei einer Ausführungsform ist der weitere Wirkstoff Dexamphatamin oderIn one embodiment, the further active ingredient is dexamphatamine or
Amphetamin.Amphetamine.
Bei einer Ausführungsform ist der weitere Wirkstoff Fenfluramin oder Dexfenfluramin.In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.
Bei noch einer Ausführungsform ist der weitere Wirkstoff Sibutramin.In another embodiment, the further active ingredient is sibutramine.
Bei einer Ausführungsform ist der weitere Wirkstoff Orlistat. Bei einer Ausführungsform ist der weitere Wirkstoff Mazindol oder Phentermin.In one embodiment, the further active ingredient is orlistat. In one embodiment, the further active ingredient is mazindol or phentermine.
Bei einer Ausführungsform werden die Verbindungen der Formel I in Kombination mit Ballaststoffen, vorzugsweise unlöslichen Ballaststoffen (siehe z.B. Carob/ Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax ist ein Carob enthaltendes Produkt der Fa. Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) verabreicht. Die Kombination mit Caromax® kann in einer Zubereitung erfolgen, oder durch getrennte Gabe von Verbindungen der Formel I und Caromax®. Caromax® kann dabei auch in Form von Lebensmitteln, wie z.B. in Backwaren oder Müsliriegeln, verabreicht werden.In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)). The combination with Caromax ® can be done in one preparation or by separate administration of compounds of formula I and Caromax ® . Caromax ® can also be administered in the form of food, such as in baked goods or granola bars.
Es versteht sich, dass jede geeignete Kombination der erfindungsgemäßen Verbindungen mit einer oder mehreren der vorstehend genannten Verbindungen und wahlweise einer oder mehreren weiteren pharmakologisch wirksamen Substanzen als unter den Schutzbereich der vorliegenden Erfindung fallend angesehen wird. It goes without saying that any suitable combination of the compounds according to the invention with one or more of the abovementioned compounds and optionally one or more further pharmacologically active substances is considered to be within the scope of the present invention.
JTT-501 Die nachfolgend aufgeführten Beispiele dienen zur Erläuterung der Erfindung, ohne diese jedoch einzuschränken.JTT-501 The examples listed below serve to illustrate the invention, but without restricting it.
Ein exakt analoges Beispiel zu Verbindungen der Formel I ist in WO 9946236 nicht aufgeführt. Als ähnlichste Verbindung wurde deshalb Vergleichsbeispiel A ausgewählt. Die Verbindungen dieser Anmeldung heben sich von dem Vergleichsbeispiel A durch eine erhöhte Aktivität an der Glycogen Phosphorylase a ab, siehe Tabelle 2. An exactly analogous example to compounds of formula I is not listed in WO 9946236. Comparative example A was therefore selected as the most similar compound. The compounds of this application stand out from Comparative Example A by an increased activity on the glycogen phosphorylase a, see Table 2.
Vergleichsbeispiel A:Comparative Example A:
Tabelle 1 : Beispiele der FormelTable 1: Examples of the formula
liegt als Trifluoressigsäuresalz vor is present as the trifluoroacetic acid salt
Von allen aufgeführten Beispielen wurde ein Massenspektrum oder HPLC/MS gemessen und in diesem der Molpeak (Molmasse H+) nachgewiesen. A mass spectrum or HPLC / MS was measured from all the examples listed and the mol peak (mol mass H + ) was detected in this.
Die Wirksamkeit der Verbindungen wurde wie folgt getestet:The effectiveness of the compounds was tested as follows:
Glykogenphosphorylase a AktivitätstestGlycogen phosphorylase a activity test
5 Der Effekt von Verbindungen auf die Aktivität der aktiven Form der Glykogenphosphorylase (GPa) wurde in der umgekehrten Richtung, durch Verfolgen der Glykogensynthese aus Glukose-1 -Phosphat an Hand der Bestimmung der Freisetzung von anorganischem Phosphat, gemessen. Alle Reaktionen wurden als Doppelbestimmungen in Mikrotiterplatten mit 96-Vertiefungen (Half Area Plates,5 The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the opposite direction by monitoring glycogen synthesis from glucose-1-phosphate by determining the release of inorganic phosphate. All reactions were carried out as duplicate determinations in microtiter plates with 96-wells (half area plates,
10 Costar Nr. 3696) durchgeführt, wobei die Änderung der Absorption auf Grund der Bildung des Reaktionsprodukts bei der weiter unten spezifizierten Wellenlänge in einem Multiskan Ascent Elisa Reader (Lab Systems, Finnland) gemessen wurde. Um die GPa Enzymaktivität in der umgekehrten Richtung zu messen, wurde die Umwandlung von Glukose-1 -Phosphat in Glykogen und anorganisches Phosphat nach10 Costar No. 3696), the change in absorption due to the formation of the reaction product at the wavelength specified below being measured in a Multiskan Ascent Elisa Reader (Lab Systems, Finland). In order to measure the GPa enzyme activity in the opposite direction, the conversion of glucose-1-phosphate into glycogen and inorganic phosphate was followed
15 der allgemeinen Methode von Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970 Jul;48(7):746-754) mit folgenden Modifikationen gemessen: Humane Glykogenphosphorylase a (zum Beispiel mit 0,76 mg Protein / ml (Aventis Pharma Deutschland GmbH), gelöst in Pufferlösung E (25 mM ?-Glyzerophosphat, pH 7,0, 1 mM EDTA und 1 mM Dithiotreitol) wurde mit Puffer T (50 mM Hepes, pH 7,0,15 the general method of Engers et al. (Engers HD, Shechosky S, Madsen NB, Can J Biochem 1970 Jul; 48 (7): 746-754) measured with the following modifications: Human glycogen phosphorylase a (for example with 0.76 mg protein / ml (Aventis Pharma Deutschland GmbH) dissolved in buffer solution E (25 mM? glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiotreitol) was mixed with buffer T (50 mM Hepes, pH 7.0,
20 100 mM KCl, 2,5 mM EDTA, 2,5 mM MgCI26H20) und Zusatz von 5 mg/ml Glykogen auf eine Konzentration von 10 μg Protein/ml verdünnt. Prüfsubstanzen wurden als 10 mM Lösung in DMSO zubereitet und auf 50 μM mit Pufferlösung T verdünnt. Zu 10 μl dieser Lösung wurden 10 μl 37,5 mM Glukose, gelöst in Pufferlösung T und 5 mg/mL Glykogen, sowie 10 μl einer Lösung von humaner Glykogenphosphorylase a (10 μg20 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl 2 6H 2 0) and addition of 5 mg / ml glycogen diluted to a concentration of 10 μg protein / ml. Test substances were prepared as a 10 mM solution in DMSO and diluted to 50 μM with buffer solution T. 10 μl of this solution were mixed with 10 μl of 37.5 mM glucose, dissolved in buffer solution T and 5 mg / ml glycogen, and 10 μl of a solution of human glycogen phosphorylase a (10 μg
25 Protein/ml) und 20 μl Glukose-1 -Phosphat, 2,5 mM zugegeben. Der basale Wert der Glykogenphosphorylase a Aktivität in Abwesenheit von Prüfsubstanz wurde durch Zugabe von 10 μl Pufferlösung T (0,1 % DMSO) bestimmt. Die Mischung wurde 40 Minuten bei Raumtemperatur inkubiert und das freigesetzte anorganische Phosphat mittels der allgemeinen Methode von Drueckes et al. (Drueckes P, Schinzel R, Palm25 protein / ml) and 20 ul glucose-1-phosphate, 2.5 mM added. The basal value of glycogen phosphorylase a activity in the absence of test substance was determined by adding 10 μl of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes and the inorganic phosphate released by the general method of Drueckes et al. (Press P, Schinzel R, Palm
30 D, Anal Biochem 1995 Sep 1 ;230(1 ):173-177) mit folgenden Modifikationen gemessen: 50 μl einer Stop-Lösung von 7,3 mM Ammoniummolybdat, 10,9 mM Zinkacetat, 3,6 % Askorbinsäure, 0,9 % SDS werden zu 50 μl der Enzymmischung gegeben. Nach 60 Minuten Inkubation bei 45 °C wurde die Absorption bei 820 nm gemessen. Zur Bestimmung der Hintergrundsabsorption wurde in einem separaten Ansatz die Stop- Lösung unmittelbar nach Zugabe der Glukose-1 -Phosphatlösung zugegeben. Dieser Test wurde mit einer Konzentrationen von 10 μM der Prüfsubstanz durchgeführt, um die jeweilige Hemmung der Glykogenphosphorylase a in vitro durch die Prüfsubstanz zu bestimmen.30 D, Anal Biochem 1995 Sep 1; 230 (1): 173-177) measured with the following modifications: 50 μl of a stop solution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid, 0. 9% SDS are added to 50 μl of the enzyme mixture. After 60 Minutes incubation at 45 ° C, the absorption was measured at 820 nm. To determine the background absorption, the stop solution was added in a separate batch immediately after the addition of the glucose-1-phosphate solution. This test was carried out with a concentration of 10 μM of the test substance in order to determine the respective inhibition of glycogen phosphorylase a in vitro by the test substance.
Tabelle 2: Biologische AktivitätTable 2: Biological activity
Vergleichsbeispiel A zeigt keine Inhibition bei einer Konzentration von 10μM und 11% Inhibition bei einer Konzentration von 100 μM. Aus der Tabelle ist abzulesen, dass die Verbindungen der Formel I die Aktivität der Glykogenphosphorylase a hemmen und dadurch zur Senkung des Blutzuckerspiegels gut geeignet sind. Insbesonders weisen die Verbindungen der Formel I deutlich erhöhte Wirkung gegenüber dem Vergleichsbeispiel A auf. Comparative Example A shows no inhibition at a concentration of 10 μM and 11% inhibition at a concentration of 100 μM. It can be seen from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are therefore very suitable for lowering the blood sugar level. In particular, the compounds of the formula I have a markedly increased activity compared to comparative example A.
Nachfolgend wird die Herstellung einiger Beispiele detailliert beschrieben, die übrigen Verbindungen der Formel I wurden analog erhalten:The preparation of some examples is described in detail below; the other compounds of the formula I were obtained analogously:
Experimenteller Teil:Experimental part:
Beispiel 1 : N-{3-[3-(2-Chlor-4,5-difluorbenzoyl)-ureido]-4-methoxyphenyl}-acetamidExample 1: N- {3- [3- (2-chloro-4,5-difluorobenzoyl) -ureido] -4-methoxyphenyl} acetamide
a) 2-Chlor-4,5-difluorbenzoylisocyanata) 2-chloro-4,5-difluorobenzoyl isocyanate
2-Chlor-4,5-difluorbenzamid wurde in Dichlormethan gelöst, mit 1 ,5 eq. Oxalylchlorid versetzt und 16 Stunden auf Rückfluss erhitzt. Das Reaktionsgemisch wurde am Hochvakuum eingeengt und ohne weitere Reinigung in Stufe b umgesetzt.2-chloro-4,5-difluorobenzamide was dissolved in dichloromethane with 1, 5 eq. Oxalyl chloride was added and the mixture was heated to reflux for 16 hours. The reaction mixture was concentrated in a high vacuum and reacted in step b without further purification.
b) 1-(2-Chlor-4,5-difluorbenzoyl)-3-(2-methoxy-5-nitrophenyl)-harnstoffb) 1- (2-Chloro-4,5-difluorobenzoyl) -3- (2-methoxy-5-nitrophenyl) urea
1 g (5,9 mmol) 2-Methoxy-5-nitroanilin wurden mit 1 ,3 g (5,9 mmol) 2-Chloro-4,5- difluorbenzoylisocyanat aus Stufe a in 2 ml N-Methylpyrrolidon versetzt und eine Stunde bei Raumtemperatur zur Reaktion gebracht. Der Niederschlag wurde abfiltriert, zweimal mit je 5 ml Acetonitril gewaschen und im Hochvakuum getrocknet. Man erhielt 2,2 g des gewünschten Produktes, das ohne weitere Aufreinigung in Stufe c eingesetzt wurde.1 g (5.9 mmol) of 2-methoxy-5-nitroaniline were mixed with 1.3 g (5.9 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from stage a in 2 ml of N-methylpyrrolidone and added for one hour Brought to reaction at room temperature. The precipitate was filtered off, washed twice with 5 ml of acetonitrile and dried in a high vacuum. 2.2 g of the desired product were obtained, which was used in step c without further purification.
c) 1-(2-Chlor-4,5-difluorbenzoyl)-3-(5-amino-2-methoxy-phenyl)-harnstoffc) 1- (2-Chloro-4,5-difluorobenzoyl) -3- (5-amino-2-methoxyphenyl) urea
2,2 g (5,7 mmol) 1-(2-Chlor-4,5-difluorbenzoyl)-3-(2-methoxy-5-nitrophenyl)-hamstoff wurden in 50 ml Essigsäureethylester auf Siedetemperatur erhitzt und mit 6,4 g (28,5 mmol) SnCI2 Monohydrat versetzt. Nach 1 Stunde ließ man auf Raumtemperatur abkühlen und stellte mit 2 N Natronlauge auf pH 8. Der entstandene Niederschlag wurde abfiltriert und mit Methanol gewaschen, die Mutterlauge wurde zweimal mit H20 gewaschen, getrocknet und im Vakuum eingeengt. Das entstandene Produkt (1 ,4 g) wurde ohne weitere Reinigung in Stufe d umgesetzt. d) N-{3-[3-(2-Chlor-4,5-difluorbenzoyl)-ureido]-4-methoxyphenyl}-acetamid2.2 g (5.7 mmol) of 1- (2-chloro-4,5-difluorobenzoyl) -3- (2-methoxy-5-nitrophenyl) urea were heated to boiling temperature in 50 ml of ethyl acetate and 6.4 g (28.5 mmol) of SnCl 2 monohydrate were added. After 1 hour, the mixture was allowed to cool to room temperature and adjusted to pH 8 with 2N sodium hydroxide solution. The precipitate formed was filtered off and washed with methanol, the mother liquor was washed twice with H 2 O, dried and concentrated in vacuo. The resulting product (1.4 g) was reacted in step d without further purification. d) N- {3- [3- (2-Chloro-4,5-difluorobenzoyl) -ureido] -4-methoxyphenyl} acetamide
0,10 g (0,3 mmol) 1-(2-Chlor-4,5-difluorbenzoyl)-3-(5-amino-2-methoxy-phenyl)- harnstoff wurden mit 1 ml N-Methylpyrrolidon, 0,11 g (0,3 mmol) Acetanhydrid versetzt und 2 Stunden bei Raumtemperatur gerührt. Es wurde mit 20 ml H20 verdünnt und dreimal mit je 20 ml Essigsäureethylester extrahiert. Die vereinigte organische Phase wurde mit H20 gewaschen, getrocknet und eingeengt. Das Rohprodukt wurde durch präparative HPLC (Säule: Waters Xterra™MS C18, 5 μm, 30x100 mm, Laufmittel: A: H20 + 0,2 % Trifluoressigsäure, B: Acetonitril, Gradient: 2,5 Minuten 90 % A / 10 % B bis 17,5 Minuten 10 % A / 90 % B) gereinigt. Man erhielt 0,03 g des gewünschten Produktes. Schmelzpunkt 225-228 °C0.10 g (0.3 mmol) of 1- (2-chloro-4,5-difluorobenzoyl) -3- (5-amino-2-methoxyphenyl) urea were mixed with 1 ml of N-methylpyrrolidone, 0.11 g (0.3 mmol) of acetic anhydride are added and the mixture is stirred at room temperature for 2 hours. It was diluted with 20 ml of H 2 O and extracted three times with 20 ml of ethyl acetate. The combined organic phase was washed with H 2 0, dried and concentrated. The crude product was purified by preparative HPLC (column: Waters Xterra ™ MS C 18 , 5 μm, 30x100 mm, eluent: A: H 2 0 + 0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A / 10% B to 17.5 minutes 10% A / 90% B) cleaned. 0.03 g of the desired product was obtained. Melting point 225-228 ° C
Analog zu Beispiel 1 wurden die Beispiele 2-8, 27-62 und 78-88 aus den entsprechenden Nitroanilinen und den entsprechenden Isocyanaten ggf. unter Verwendung üblicher Schutzgruppentechniken hergestellt.Analogously to Example 1, Examples 2-8, 27-62 and 78-88 were prepared from the corresponding nitroanilines and the corresponding isocyanates, if necessary using customary protecting group techniques.
Beispiel 64: N-{3-[3-(2-Chlor-4,5-difluorbenzoyl)-ureido]-4-trifluormethoxyphenyl}- acetamidExample 64: N- {3- [3- (2-chloro-4,5-difluorobenzoyl) -ureido] -4-trifluoromethoxyphenyl} acetamide
a) 3-Nitro-4-trifluormethoxyanilina) 3-Nitro-4-trifluoromethoxyaniline
Vorschrift nach Syn. Commun. 1988, 18 (16+17), 2161-2165Regulation according to Syn. Commun. 1988, 18 (16 + 17), 2161-2165
3,0 g (17 mmol) 4-Trifluormethoxyanilin wurden in 10 ml konz. Schwefelsäure gelöst, auf 0-10 °C gekühlt und portionsweise mit 2,1 g (17 mmol) Harnstoff nitrat versetzt, so dass die Temperatur nicht 10 °C überstieg. Nach Ende der Zugabe wurde noch 10 Minuten nachgerührt und dann die Lösung auf Eis gegossen. Es wurde mit Dichlormethan extrahiert, die vereinigten organischen Phasen getrocknet und das Lösungsmittel im Vakuum abdestilliert. Das Produkt wurde ohne weitere Aufreinigung in die nächste Stufe eingesetzt (Ausbeute 2,8 g, 75 %). Das so erhaltene 3-Nitro-4-trifluormethoxyaniIin wurde entsprechend der Vorschrift d für Beispiel 1 mit Acetylchlorid umgesetzt, mit Wasserstoff in Gegenwart von Pd/C hydriert und mit 2-Chlor-4,5-difluorbenzoylisocyanat zum Acylharnstoff umgesetzt. Schmelzpunkt 216-218 °C3.0 g (17 mmol) of 4-trifluoromethoxyaniline were concentrated in 10 ml. Dissolved sulfuric acid, cooled to 0-10 ° C and mixed in portions with 2.1 g (17 mmol) of urea nitrate so that the temperature did not exceed 10 ° C. After the addition had ended, the mixture was stirred for a further 10 minutes and then the solution was poured onto ice. It was extracted with dichloromethane, the combined organic phases were dried and the solvent was distilled off in vacuo. The product was used in the next step without further purification (yield 2.8 g, 75%). The 3-nitro-4-trifluoromethoxyaniline obtained in this way was reacted with acetyl chloride in accordance with instructions d for Example 1, hydrogenated with hydrogen in the presence of Pd / C and reacted with 2-chloro-4,5-difluorobenzoyl isocyanate to give the acylurea. Melting point 216-218 ° C
Analog wurden die Beispiele 65 bis 70 hergestellt, indem andere Acylierungsmittel entsprechend Beispiel 1d eingesetzt wurden.Examples 65 to 70 were prepared analogously, using other acylating agents as in Example 1d.
Beispiel 73: N-{3-[3-(2-Chlor-4,5-difluorbenzoyl)-ureido]-4-pyrrolidin-1-yl-phenyl}- acetamidExample 73: N- {3- [3- (2-Chloro-4,5-difluorobenzoyl) -ureido] -4-pyrrolidin-1-yl-phenyl} acetamide
a) N-(2-Fluor-5-nitrophenyl)-acetamida) N- (2-Fluoro-5-nitrophenyl) acetamide
5,0 g (32 mmol) 2-Fluor-5-nitroanilin wurden mit 10 ml (110 mmol) Acetanhydrid und 0,1 ml konz. Schwefelsäure versetzt und 1 ,5 Stunden bei 100 °C gerührt. Die Lösung wurde auf 100 ml Eis/Wasser gegeben, der dabei gebildete Niederschlag abfiltriert und mit Wasser gewaschen. Das Rohprodukt wurde durch Chromatographie (Essigsäureethylester/Heptan 1 :1) an Kieselgel gereinigt (Ausbeute 5,4 g, 85 %). Schmelzpunkt 174-176 °C5.0 g (32 mmol) of 2-fluoro-5-nitroaniline were concentrated with 10 ml (110 mmol) of acetic anhydride and 0.1 ml. Added sulfuric acid and stirred at 100 ° C for 1.5 hours. The solution was poured onto 100 ml of ice / water, the precipitate formed was filtered off and washed with water. The crude product was purified by chromatography (ethyl acetate / heptane 1: 1) on silica gel (yield 5.4 g, 85%). Melting point 174-176 ° C
b) N-(5-Nitro-2-pyrrolidin-1 -yl-phenyl)-acetamidb) N- (5-nitro-2-pyrrolidin-1-yl-phenyl) -acetamide
0,5 g (2,5 mmol) N-(2-Fluor-5-nitrophenyl)-acetamid wurden in einem Druckreaktionsgefäß mit 1 ml (12,6 mmol) Pyrrolidin versetzt und 2,5 Stunden bei0.5 g (2.5 mmol) of N- (2-fluoro-5-nitrophenyl) acetamide were mixed with 1 ml (12.6 mmol) of pyrrolidine in a pressure reaction vessel and added for 2.5 hours
90 °C gerührt. Nach dem Abkühlen wurde mit 20 ml Dichlormethan verdünnt, mit90 ° C stirred. After cooling, the mixture was diluted with 20 ml of dichloromethane
Zitronensäurelösung (10 %) auf pH 4 eingestellt und viermal mit Wasser gewaschen.Citric acid solution (10%) adjusted to pH 4 and washed four times with water.
Nach dem Trocknen der organischen Phase wurde das Lösungsmittel im Vakuum abdestilliert. In der wässrigen Phase fiel ein Niederschlag aus. Dieser wurde abfiltriert, mit Wasser gewaschen und mit dem Rückstand aus der organischen Phase vereinigtAfter the organic phase had dried, the solvent was distilled off in vacuo. A precipitate precipitated out in the aqueous phase. This was filtered off, washed with water and combined with the residue from the organic phase
(Ausbeute 0,58 g, 93 %). Das Produkt wurde ohne weitere Aufreinigung in Stufe c umgesetzt. Schmelzpunkt 210-213 °C(Yield 0.58 g, 93%). The product was reacted in step c without further purification. Melting point 210-213 ° C
c) 5-Nitro-2-pyrrolidin-1 -yl-anilinc) 5-nitro-2-pyrrolidin-1-yl aniline
0,58 g (2,3 mmol) N-(5-Nitro-2-pyrrolidin-1-yl-phenyl)-acetamid wurden mit 12 ml konz. Salzsäure versetzt und 1 ,5 Stunden zum Rückfluss erhitzt. Die Lösung wurde auf 100 ml Eis/Wasser gegeben, mit 2 N Natronlauge neutralisiert und dreimal mit Essigsäureethylester extrahiert. Nach dem Trocknen wurde das Lösungsmittel im Vakuum abdestilliert, wobei man das Produkt quantitativ als roten Feststoff erhielt, das ohne weitere Aufreinigung in für Beispiel 1 beschriebenen Reaktionen a-d (Umsetzung mit dem Acylisocyanat, Reduktion mit SnCI2 und Acylierung mit Ac20) eingesetzt wurde. Schmelzpunkt 175-180 °C0.58 g (2.3 mmol) of N- (5-nitro-2-pyrrolidin-1-yl-phenyl) acetamide were mixed with 12 ml of conc. Hydrochloric acid added and heated to reflux for 1.5 hours. The solution was added to 100 ml of ice / water, neutralized with 2N sodium hydroxide solution and extracted three times with ethyl acetate. After drying, the solvent was distilled off in vacuo to give the product quantitatively as a red solid, which was used without further purification in reactions described for Example 1 ad (reaction with the acyl isocyanate, reduction with SnCl 2 and acylation with Ac 2 O) , Melting point 175-180 ° C
Analog zu Beispiel 73 wurden die Beispiele 71 , 72 und 74-77 aus den entsprechenden Aminen und den jeweiligen Acylierungsmitteln ggf. unter Verwendung üblicher Schutzgruppentechniken hergestellt.Analogously to Example 73, Examples 71, 72 and 74-77 were prepared from the corresponding amines and the respective acylating agents, if appropriate using conventional protecting group techniques.
Bei der Synthese der Beispiele 19-26 und 63 wurde 4-Amino-3-methoxybenzoesäure analog Beispiel 64a mit Harnstoffnitrat nitriert. Der sich daran anschließende Syntheseweg verlief entsprechend dem in Beispiel 1 dargestellten. Zur Synthese der Beispiele 9-18 wurden N-(4-Methoxy-2-methylphenyl)-acetamid bzw. N-(2-Methoxy-4-methylphenyl)-acetamid unter üblichen Bedingungen (HN03/HOAc) nitriert, das Amid mit konz. Salzsäure gespalten (analog zu Beispiel 73c) und weiter umgesetzt, wie es für Beispiel 1 beschrieben ist. In the synthesis of Examples 19-26 and 63, 4-amino-3-methoxybenzoic acid was nitrated with urea nitrate analogously to Example 64a. The subsequent synthetic route was the same as that shown in Example 1. To synthesize Examples 9-18, N- (4-methoxy-2-methylphenyl) acetamide or N- (2-methoxy-4-methylphenyl) acetamide were nitrated under normal conditions (HN0 3 / HOAc), the amide with conc. Cleaved hydrochloric acid (analogously to Example 73c) and reacted further as described for Example 1.

Claims

Patenansprüche:Patent claims:
Verbindungen der FormelCompounds of the formula
R10 R11R10 R11
worin bedeutenin what mean
R8, R9, R10, R11 unabhängig von einander H, F, Cl, Br, OH, N02, CN, 0-(d-R8, R9, R10, R11 independently of one another H, F, Cl, Br, OH, N0 2 , CN, 0- (d-
C6)-Alkyl, 0-(C2-C6)-Alkenyl, 0-(C2-C6)-Alkinyl, 0-S02-(C C4)-Alkyl, (d- C6)-Alkyl, (C2-C6)-Alkenyl oder (C2-C6)-Alkinyl, wobei Alkyl, Alkenyl und Alkinyl mehrfach durch F, Cl oder Br substituiert sein können;C 6 ) alkyl, 0- (C 2 -C 6 ) alkenyl, 0- (C 2 -C 6 ) alkynyl, 0-S0 2 - (CC 4 ) alkyl, (d- C 6 ) alkyl , (C 2 -C 6 ) alkenyl or (C 2 -C 6 ) alkynyl, where alkyl, alkenyl and alkynyl can be substituted several times by F, Cl or Br;
R1 , R2 unabhängig voneinander H, (d-C6)-Alkyl, wobei Alkyl mit OH, O-(d-d)-R1, R2 independently of one another are H, (dC 6 ) -alkyl, alkyl having OH, O- (dd) -
Alkyl, NH2, NH(C C4)-Alkyl, N[(d-C6)-Alkyl]2 substituiert sein kann, O- (C C6)-Alkyl, CO-(C1-C6)-Alkyl, COO-(d-C6)-Alkyl, (d-C6)-Alkylen- COOH oder (C C6)-Alkylen-COO-(d-C6)-alkyl;Alkyl, NH 2 , NH (CC 4 ) alkyl, N [(dC 6 ) alkyl] 2 may be substituted, O- (CC 6 ) alkyl, CO- (C 1 -C 6 ) alkyl, COO- (dC 6 ) alkyl, (dC 6 ) alkylene-COOH or (CC 6 ) alkylene-COO- (dC 6 ) alkyl;
R3, R4, R5, R6 unabhängig voneinander H, F, Cl, Br, N02, CN, 0-R12, O-R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, O-
Phenyl, S-R12, COOR12, N(R13)(R14), (C C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalky.-(C C )-alkylen oder 0-(d-C5)-Alkyl-COOR12, wobei Alkyl, Cycloalkyl, Alkylen und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12 oder N(R13)(R14) substituiert sein können; R7 H, (d-C6)-Alkyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(C C )-a]kylen,Phenyl, S-R12, COOR12, N (R13) (R14), (CC 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 ) -Cycloalkyl, (C 3 -C 7 ) -cycloalky .- (CC) -alkylene or 0- (dC 5 ) -alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl several times with F, Cl, Br, OR12, COOR12 or N (R13) (R14) may be substituted; R7 H, (dC 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (CC) -a] kylene,
(C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C1-C6)-Alkylcarboxy-(C1-C6)-alkylen, COOR12, (C6-C10)-Aryl, (C6-do)-Aryl-(d-C4)-alkylen, Heterocyclischer Rest, Heteroaryl-(C1-C4)-alkylen oder Heteroarylcarbonyl, wobei Alkyl, Cycloalkyl, Alkylen, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12, CONH2, CONH(d-C6)-Alkyl, CON[(d-C6)-Alkyl]2 oder N(R13)(R14) substituiert sein können und wobei Aryl und Heteroaryl mehrfach mit F, Cl, Br, N02, CN, 0-R12, S-R12, COOR12, N(R13)(R14), oder (d-C6)-Alkyl substituiert sein können;(C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkylcarboxy- (C 1 -C 6 ) alkylene, COOR12, (C 6 -C 10 ) - Aryl, (C 6 -do) -aryl- (dC 4 ) -alkylene, heterocyclic radical, heteroaryl- (C 1 -C 4 ) -alkylene or heteroarylcarbonyl, where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl are repeated several times with F, Cl , Br, OR12, COOR12, CONH 2 , CONH (dC 6 ) -alkyl, CON [(dC 6 ) -alkyl] 2 or N (R13) (R14) and where aryl and heteroaryl are substituted several times with F, Cl, Br, N0 2 , CN, 0-R12, S-R12, COOR12, N (R13) (R14), or (dC 6 ) -alkyl may be substituted;
R12 H, (Cι-C8)-Alkyl, (C2-C8)-Alkenyl oder (C2-C8)-Alkinyl, wobei Alkyl, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OH oder 0-(Cι-C4)-Alkyl substituiert sein können,R12 H, (-CC 8 ) -alkyl, (C 2 -C 8 ) -alkenyl or (C 2 -C 8 ) -alkynyl, alkyl, alkenyl and alkynyl being used repeatedly with F, Cl, Br, OH or 0- (C 1 -C 4 ) -alkyl can be substituted,
R13, R14 unabhängig voneinander H, (C C8)-Alkyl, (C2-C8)-Alkenyl, (C2-C8)-Alkinyl, (C3-C7)-Cycloalkyl , (C3-C7)-Cycloalkyl-(d -C4)-alkylen , COO-(Cι -C4)-Al kyl , COO-(C2-C4)-Alkenyl, Phenyl oder S02-Phenyl, wobei der Phenylring bis zu zweifach mit F, Cl, CN, OH, (C C6)-Alkyl, 0-(d-C6)-Alkyl, CF3, OCF3, COOH, COO(d-C6)-Alkyl oder CONH2 substituiert sein kann; wobei R13 und R14 gemeinsam mit dem Stickstoffatom an das sie gebunden sind einen 3-7 gliedrigen, gesättigten heterozyklischen Ring bilden können, der bis zu 2 weitere Heteroatome aus der Gruppe N, O oder S enthalten kann, wob-ei der heterocyclische Ring bis zu dreifach mit F, Cl, Br, OH, Oxo, N(R21 )(R22) oder (Cι-C4)-Alkyl substituiert sein kann;R13, R14 independently of one another are H, (CC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (d -C 4 ) alkylene, COO- (-C -C 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring up to two times may be substituted with F, Cl, CN, OH, (CC 6 ) alkyl, 0- (dC 6 ) alkyl, CF 3 , OCF 3 , COOH, COO (dC 6 ) alkyl or CONH 2 ; where R13 and R14 together with the nitrogen atom to which they are attached can form a 3-7-membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, the heterocyclic ring up to can be substituted three times with F, Cl, Br, OH, oxo, N (R21) (R22) or (-CC 4 ) alkyl;
R21 , R22 unabhängig voneinander H, (C C8)-Alkyl, (C2-C8)-Alkenyl, (C2-C8)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(Cι-C4)-alkylen, COO-(Cι-C4)-Alkyl, COO-(C2-C4)-Alkenyl, Phenyl oder S02-Phenyl, wobei der Phenylring bis zu zweifach mit F, Cl, CN, OH, (C C6)-Alkyl, 0-(d-C6)-Alkyl, CF3, OCF3, COOH, COO(d-C6)-Alkyl oder CONH2 substituiert sein kann; wobei Verbindungen der Formel I ausgenommen sind, in denen die Reste gleichzeitig die folgenden Bedeutung haben:R21, R22 independently of one another are H, (CC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (-C-C 4 ) alkylene, COO- (-C-C 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring with up to twice F, Cl, CN, OH, (CC 6 ) alkyl, 0- (dC 6 ) alkyl, CF 3 , OCF 3 , COOH, COO (dC 6 ) alkyl or CONH 2 may be substituted; with the exception of compounds of the formula I in which the radicals simultaneously have the following meaning:
R5 gleich Halogen oder unsubstituiertes (d-CβJ-Alkyl, R7 gleich Heterocyclischer Rest oder Heteroaryl;R5 is halogen or unsubstituted (d-CβJ-alkyl, R7 is heterocyclic radical or heteroaryl;
sowie deren physiologisch verträgliche Salze.and their physiologically tolerable salts.
2. Verbindungen der Formel I, gemäß Anspruch 1 , dadurch gekennzeichnet, daß darin bedeuten2. Compounds of formula I, according to claim 1, characterized in that mean
R8, R9, R10, R11 unabhängig von einander H, F, Cl, Br, OH, N02, CN, 0-(d-R8, R9, R10, R11 independently of one another H, F, Cl, Br, OH, N0 2 , CN, 0- (d-
C6)-Alkyl, wobei Alkyl mehrfach durch F, Cl oder Br substituiert sein kann;C 6 ) -alkyl, where alkyl can be substituted several times by F, Cl or Br;
R1 , R2 H;R1, R2 H;
R3, R4, R5, R6 unabhängig voneinander H, F, Cl, Br, N02, CN, 0-R12, O-R3, R4, R5, R6 independently of one another H, F, Cl, Br, N0 2 , CN, 0-R12, O-
Phenyl, S-R12, COOR12, N(R13)(R14), (d-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(C1-C4)-alkylen oder 0-(Cι-C5)-Alkyl-COOR12, wobei Alkyl, Cycloalkyl, Alkylen und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12 oder N(R13)(R14), substituiert sein können;Phenyl, S-R12, COOR12, N (R13) (R14), (dC 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 ) -Cycloalkyl, (C 3 -C 7 ) -cycloalkyl- (C 1 -C 4 ) -alkylene or 0- (Cι-C 5 ) -alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl have multiple F, Cl, Br, OR12, COOR12 or N (R13) (R14) may be substituted;
R7 H, (d-C6)-Alkyl, (C3-C7)-Cycloalkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyi, (d- C6)-Alkylcarboxy-(d-C6)-alkylen, COOR12, (C6-C10)-Aryl, (C6-C10)-Aryl-R7 H, (dC 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (d- C 6 ) alkylcarboxy- ( dC 6 ) alkylene, COOR12, (C 6 -C 10 ) aryl, (C 6 -C 10 ) aryl
(CrC4)-alkylen, Heteroaryl, Heteroaryl-(CrC4)-alkylen oder(CrC 4 ) alkylene, heteroaryl, heteroaryl (CrC 4 ) alkylene or
Heteroarylcarbonyl, wobei Alkyl, Cycloalkyl, Alkylen, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OR12, COOR12, CONH2, CONH(d-C6)-Alkyl, CON[(C C6)-Alkyl]2 oder N(R13)(R14) substituiert sein können und wobei Aryl und Heteroaryl mehrfach mit F, Cl, Br, N02, CN, 0-R12, S-R12,Heteroarylcarbonyl, where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl multiple times with F, Cl, Br, OR12, COOR12, CONH 2 , CONH (dC 6 ) -alkyl, CON [(CC 6 ) -alkyl] 2 or N (R13) (R14) can be substituted and where aryl and heteroaryl are repeated several times with F, Cl, Br, N0 2 , CN, 0-R12, S-R12,
COOR12, N(R13)(R14), oder (Cι-C6)-Alkyl substituiert sein können; R12 H, (d-C8)-Alkyl, (C2-C8)-Alkenyl oder (C2-C8)-Alkinyl, wobei Alkyl, Alkenyl und Alkinyl mehrfach mit F, Cl, Br, OH oder 0-(d-C4)-Alkyl substituiert sein können,COOR12, N (R13) (R14), or (-C-C 6 ) alkyl may be substituted; R12 is H, (dC 8 ) -alkyl, (C 2 -C 8 ) -alkenyl or (C 2 -C 8 ) -alkynyl, where alkyl, alkenyl and alkynyl are used repeatedly with F, Cl, Br, OH or 0- (dC 4 ) alkyl can be substituted,
R13, R14 unabhängig voneinander H, (C C8)-Alkyl, (C2-C8)-Alkenyl, (C2-C8)-Alkinyl, (C3-C7)-Cycloalkyl, (C3-C7)-Cycloalkyl-(Cι-C4)-alkylen, COO-(d-C4)-Alkyl, COO-(C2-C4)-Alkenyl, Phenyl oder S02-Phenyl, wobei der Phenylring bis zu zweifach mit F, Cl, CN, OH, (C C6)-Alkyl, 0-(d-C6)-Alkyl, CF3, OCF3, COOH, COO(d-C6)-Alkyl oder CONH2 substituiert sein kann; wobei R13 und R14 gemeinsam mit dem Stickstoffatom an das sie gebunden sind einen 3-7 gliedrigen, gesättigten heterozyklischen Ring bilden können, der bis zu 2 weitere Heteroatome aus der Gruppe N, O oder S enthalten kann, wobei der heterocyclische Ring bis zu dreifach mit F, Cl, Br, OH, Oxo, N(R21 )(R22) oder (d-d)-Alkyl substituiert sein kann;R13, R14 independently of one another are H, (CC 8 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) -Cycloalkyl- (-C-C 4 ) alkylene, COO- (dC 4 ) alkyl, COO- (C 2 -C 4 ) alkenyl, phenyl or S0 2 -phenyl, the phenyl ring being up to twice with F, Cl, CN, OH, (CC 6 ) alkyl, 0- (dC 6 ) alkyl, CF 3 , OCF 3 , COOH, COO (dC 6 ) alkyl or CONH 2 may be substituted; where R13 and R14 together with the nitrogen atom to which they are attached can form a 3-7 membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S, the heterocyclic ring having up to three times with F, Cl, Br, OH, Oxo, N (R21) (R22) or (dd) alkyl may be substituted;
R21 , R22 unabhängig voneinander H, (C C8)-Alkyl;R21, R22 independently of one another are H, (CC 8 ) -alkyl;
wobei Verbindungen der Formel I ausgenommen sind, in denen die Reste gleichzeitig die folgenden Bedeutung haben: R5 gleich Halogen oder unsubstituiertes (C C6)-Alkyl, R7 gleich Heterocyclischer Rest oder Heteroaryl;with the exception of compounds of the formula I in which the radicals simultaneously have the following meaning: R5 is halogen or unsubstituted (CC 6 ) alkyl, R7 is heterocyclic radical or heteroaryl;
sowie deren physiologisch verträgliche Salze.and their physiologically tolerable salts.
3. Verbindungen der Formel l, gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß darin bedeuten3. Compounds of formula I, according to claim 1 or 2, characterized in that mean
R8, R9, R10, R11 unabhängig von einander H, F oder Cl;R8, R9, R10, R11 independently of one another H, F or Cl;
R1 , R2, R4, R6 H; R3, R5 unabhängig voneinander H, Cl, OR12, COOR12, N(R13)(R14) oder (d-R1, R2, R4, R6 H; R3, R5 independently of one another H, Cl, OR12, COOR12, N (R13) (R14) or (d-
C6)-Alkyl;C 6 ) alkyl;
R7 (C C6)-Alkyl, wobei - Alkyl mehrfach mit F, OR12, COOR12 oder N(R13)(R14) substituiert sein kann, (C3-C6)-Cycloalkyl, (C2-C6)-Alkenyl,R7 (CC 6 ) alkyl, where - alkyl can be substituted several times with F, OR12, COOR12 or N (R13) (R14), (C 3 -C 6 ) cycloalkyl, (C 2 -C 6 ) alkenyl,
(C2-C6)-Alkinyl, (d-C5)-Alkylcarboxy-(CrC6)-alkylen, COOR12, Phenyl, wobei Phenyl mehrfach mit F, OMe oder OCF3 substituiert sein kann, Benzyl, wobei dessen Phenylring mit OMe substituiert sein kann, Pyridyl, Thienyl, Furanyl, Indolylcarbonyl, Benzofuranyl, wobei Benzofuranyl mit Cl oder OMe substituiert sein kann;(C 2 -C 6 ) alkynyl, (dC 5 ) alkylcarboxy- (CrC 6 ) alkylene, COOR12, phenyl, where phenyl can be substituted several times with F, OMe or OCF 3 , benzyl, the phenyl ring of which is substituted with OMe may be pyridyl, thienyl, furanyl, indolylcarbonyl, benzofuranyl, where benzofuranyl may be substituted with Cl or OMe;
R12 H oder (Cι-C8)-Alkyl, wobei Alkyl mehrfach mit F substituiert sein kann;R12 H or (-CC 8 ) alkyl, where alkyl can be substituted several times with F;
R13, R14 unabhängig voneinander H oder (d-C8)-Alkyl; und wobeiR13, R14 independently of one another are H or (dC 8 ) -alkyl; and where
R13 und R14 gemeinsam mit dem Stickstoffatom an das sie gebunden sind einen 5- gliedrigen, gesättigten heterocyclischen Ring bilden können;R13 and R14 together with the nitrogen atom to which they are attached can form a 5-membered, saturated heterocyclic ring;
wobei Verbindungen der Formel I ausgenommen sind, in denen die Reste gleichzeitig die folgenden Bedeutung haben:with the exception of compounds of the formula I in which the radicals simultaneously have the following meaning:
R5 gleich Halogen oder unsubstituiertes (d-C6)-Alkyl, R7 gleich Heterocyclischer Rest oder Heteroaryl;R5 is halogen or unsubstituted (dC 6 ) alkyl, R7 is heterocyclic radical or heteroaryl;
sowie deren physiologisch verträgliche Salze.and their physiologically tolerable salts.
4. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3.4. Medicament containing one or more of the compounds according to one or more of claims 1 to 3.
5. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 und ein oder mehrere Blutzucker senkende Wirkstoffe. 5. Medicament containing one or more of the compounds according to one or more of claims 1 to 3 and one or more blood sugar-lowering active ingredients.
6. Arzneimittel enthaltend eine oder mehrere der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 und ein oder mehrere Statine.6. Medicament containing one or more of the compounds according to one or more of claims 1 to 3 and one or more statins.
5 7. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 zur Herstellung eines Medikamentes zur Behandlung des Typ 2 Diabetes.5 7. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for the treatment of type 2 diabetes.
8. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 zur Herstellung eines Medikamentes zur Blutzuckersenkung.8. Use of the compounds according to one or more of claims 1 to 3 for the manufacture of a medicament for lowering blood sugar.
1010
9. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 in Kombination mit mindestens einem weiteren Blutzucker senkenden Wirkstoff zur Herstellung eines Medikamentes zur Behandlung des Typ 2 Diabetes.9. Use of the compounds according to one or more of claims 1 to 3 in combination with at least one further blood sugar-lowering active ingredient for the manufacture of a medicament for the treatment of type 2 diabetes.
15 10. Verwendung der Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3 in Kombination mit mindestens einem weiteren Blutzucker senkenden Wirkstoff zur Herstellung eines Medikamentes zur Blutzuckersenkung.15 10. Use of the compounds according to one or more of claims 1 to 3 in combination with at least one further blood sugar-lowering active ingredient for the manufacture of a medicament for lowering blood sugar.
11. Verfahren zur Herstellung eines Arzneimittels enthaltend eine oder mehrere der 20 Verbindungen gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass der Wirkstoff mit einem pharmazeutisch geeigneten Träger vermischt wird und diese Mischung in eine für die Verabreichung geeignete Form , gebracht wird. 11. A process for the preparation of a medicament comprising one or more of the 20 compounds according to one or more of claims 1 to 3, characterized in that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture is brought into a form suitable for administration ,
EP04700448A 2003-01-23 2004-01-07 Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof Expired - Lifetime EP1590322B1 (en)

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